OLIGONUCLEOTIDES FOR TREATING INFLAMMATION AND NEOPLASTIC CELL PROLIFERATION

Abstract

There is provided oligonucleotides directed against the CCR3 receptor and the common beta sub-unit of IL-3, IL-5 and GMCSF receptors. The oligonucleotides are useful to inhibit general inflammation, including inflammation associated with asthma, COPD, allergy, Cystic fibrosis (CF), hypereosinophilia and neoplastic cell proliferation such as cancer.

Description

FIELD OF THE INVENTION

[0001] The invention relates to the use of antisense oligonucleotides directed against specific cellular receptors, alone or in combination, in order to inhibit general inflammation, including inflammation associated with asthma, COPD, allergy, Cystic fibrosis (CF), and hypereosinophilia. The invention also relates to the use of antisense oligonucleotides to inhibit neoplastic cell proliferation such as cancer.

BACKGROUND OF THE INVENTION

[0002] Antisense oligonucleotides (AONs) are complementary to a region of a target gene and are capable of hybridizing to the target gene sequence and inhibiting gene expression. Gene expression is inhibited through hybridization of an AON to a specific messenger RNA (mRNA) sense target according to the Watson-Crick base pairing in which adenosine and thymidine (uracil in mRNA) or guanosine and cytidine interact through hydrogen bonding. Two mechanisms are generally thought to account for these effects, the first being hybridization with impaired translation of targeted mRNA, the second being the induction of RNase H or similar enzymes with associated degradation of target mRNA. A major advantage of this strategy is the specificity of action with the potential for reduced side effects and lower toxicity, especially when applied directly to the site of action (topical treatment). This therapeutic strategy could potentially be applied to any disease in which overexpression of one or several genes is believed to be responsible for the presence or persistence of the disease. As a result, there have been numerous studies investigating the use of AONs as therapeutic agents for cancer and viral diseases.

[0003] The alveolar and airway epithelium is recognized as a dynamic barrier that plays an important role in regulating inflammatory and metabolic responses to oxidative stress, sepsis, endotoxemia, and other critical illnesses in the lung. The respiratory epithelium, in particular, is a primary target of inflammatory conditions/infections at the epithelial-blood interface, and is itself capable of amplifying an inflammatory signal by recruiting inflammatory cells and producing inflammatory mediators.

[0004] Asthma is a disease that affects 5 to 10% of the population that has doubled in prevalence in the last 25 years. This increase has been noted especially in infants after a viral infection of the airways (bronchiolitis), in children and in occupation-induced asthma. The recurrent breathing problems associated with asthma are often triggered by allergens but the exact cause of asthma remains to be elucidated. However, it is believed that agents such as viruses are involved in the perpetuation of the abnormal inflammation that is found in the airways of patients with asthma and, thus, the persistence of the disease.

[0005] For this reason, the current recommendation for first line therapy of asthma is a potent anti-inflammatory medication such as those containing corticosteroids and anti-leukotrienes. Although this approach is effective in many patients, some patients are not controlled with current anti-inflammatory medications. Corticosteroids are also potent immunosuppressives with long term side effects and have not been shown to be effective in the prevention of allergy or asthma. Anti-leukotrienes have some effect in allergy and asthma but are not as effective as corticosteroids.

[0006] Several inflammatory mediators play a role in the appearance and perpetuation of inflammation in the airways of patients with asthma. Some mediators attract the inflammatory cells into the airways either through chemotaxis of eosinophils (the chemokines: RANTES, eotaxins 1, 2, 3, MCP-3, 4 that act mostly in asthmatic inflammation through a receptor called CCR3) or through endothelial cell activation (IL-4, -13). Other mediators cause the priming and increased survival of inflammatory cells in the airways (IL-3, -4, -5, GM-CSF). These mediators thus consist of either specific chemokines for eosinophils or cytokines of the T helper lymphocyte type 2 phenotype (Th2: IL-3, -4, -5, -6, -9, -10, -13 and GM-CSF), (John A E. and Lukacs N W., 2003 Sarcoidosis Vasc Diffuse Lung Dis., 20:180-189; Blease et al., 2003, Expert Opin Emerg Drugs. 8:71-81). An improvement in asthma and general respiratory inflammation has been demonstrated when there is a decrease in these inflammatory mediators in the airways.

[0007] Allergy is a hypersensitivity to an allergen causing an undesirable immune response. Allergy is a disease that is extremely prevalent, for example atopic rhinitis, eczema and allergic conjunctivitis affect around 30% of the population. Allergy is characterized by abnormal IgE production and inflammation to an allergen. In the presence of IgE and allergen, effector cells, such as the mast cells degranulate and release inflammatory mediators leading to the recruitment of the same inflammatory cells that are found in asthma. In allergic rhinitis (i.e. hayfever), allergic conjunctivitis, nasal polyposis, chronic sinusitis, eczema, and atopic dermatitis, one finds the same excess in inflammatory mediators as those present in asthma. IL-4 and IL-13 are necessary for the production of IgE and the induction of the cells with a Th2 phenotype (Barnes P J., 2003, Cytokine Growth Factor Rev. 14:511-522; Schuh et al., 2003, Cytokine Growth Factor Rev. 2003, 14:503-510). Atopic disease is a generic name for allergic diseases which are developed by exposure to allergens, especially in individuals with a genetic propensity for being easily sensitized to allergens. Individuals having these predisposing factors readily develop an abnormal immune response to alimentary antigens and inhalants. Some specific examples of allergic diseases are bronchial asthma, atopic dermatitis, urticaria, allergic rhinitis, allergic conjunctivitis and allergic enterogastritis.

[0008] Chronic Obstructive Pulmonary Disease (COPD) is another example of an inflammatory airway and alveolar disease where persistent upregulation of inflammation is thought to play a role. Inflammation in COPD is characterized by increased infiltration of neutrophils, CD8 positive lymphocytes, and macrophages into the airways. Neutrophils and macrophages play an important role in the pathogenesis of airway inflammation in COPD because of their ability to release a number of mediators including elastase, metalloproteases, and oxygen radicals that promote tissue inflammation and damage. It has been suggested that inflammatory cell accumulation in the airways of patients with COPD is driven by increased release of pro-inflammatory cytokines and of chemokines that attract the inflammatory cells into the airways, activate them and maintain their presence. The cells that are present also release enzymes (like metalloproteases) and oxygen radicals which have a negative effect on tissue and perpetuate the disease. A vast array of pro-inflammatory cytokines and chemokines has been shown to be increased within the lungs of patients with COPD. Among them, important roles are played by tumor necrosis factor alpha (TNF-alpha), granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 8 (IL-8), levels of which are increased in the airways of patients with COPD.

[0009] Cystic fibrosis (CF) is yet another example of an airway inflammatory disease. Lack of CF transmembrane conductance regulator (CFTR) Cl.sup.- channel function leads to progressive pulmonary damage, and ultimately results in death. The loss of functional CFTR in airway epithelial cells promotes depletion and increased oxidation of the airway surface liquid. Activated neutrophils present in airways produce large amounts of proteases and reactive oxygen species (ROS). Together these changes are associated with reduced mucociliary clearance of bacteria, activation of epithelial cell signalling through multiple pathways, and subsequent hyperinflammatory responses in CF airways. Both the NF-kappaB pathway and Ca²+mobilization in airway epithelial cells are believed to be factors in the control of lung inflammation via regulated production of mediators such as IL-8 that participate in recruitment and activation of neutrophils, modulation of apoptosis, and control of epithelial barrier integrity. Excessive and persistent inflammation sustained by bacterial infections and an ongoing accumulation of airway neutrophils is a key factor in lung destruction in CF patients, and has prompted investigation into anti-inflammatory therapies.

[0010] Other examples of respiratory diseases where inflammation seems to play a role include: eosinophilic cough, bronchitis, acute and chronic rejection of lung allograft, sarcoidosis, pulmonary fibrosis, rhinitis and sinusitis.

[0011] Eosinophilic cough is characterized by chronic cough and the presence of inflammatory cells, mostly eosinophils, within the airways of patients in the absence of airway obstruction or hyperresponsiveness. Several cytokines and chemokines are increased in this disease, although they are mostly eosinophil directed. Eosinophils are recruited and activated within the airways and potentially release enzymes and oxygen radicals that play a role in the perpetuation of inflammation and cough.

[0012] Acute bronchitis is an acute disease that occurs during an infection or irritating event for example by pollution, dust, gas or chemicals, of the lower airways. Chronic bronchitis is defined by the presence of cough and phlegm production on most days for at least 3 months of the year, for 2 years. One can also find inflammatory cells, mostly neutrophils, with a broad array of chemokines and cytokines, within the airways in cases of acute or chronic bronchitis. These mediators are thought to play a role in the inflammation, symptoms and mucus production that occur during these diseases.

[0013] Lung transplantation is performed in patients with end stage lung disease. Acute and more importantly chronic allograft rejection occur when the inflammatory cells of our body, lymphocytes, do not recognize the donor organ as "self". Inflammatory cells are recruited by chemokines and cytokines and release a vast array of enzymes that lead to tissue destruction and in the case of chronic rejection a disease called bronchiolitis obliterans.

[0014] Sarcoidosis is a disease of unknown cause where chronic non-caseating granulomas occur within tissue. The lung is the organ most commonly affected. Lung bronchoalveolar lavage shows an increase in mostly lymphocytes, macrophages and sometimes neutrophils and eosinophils. These cells are also recruited and activated by cytokines and chemokines and are thought to be involved in the pathogenesis of the disease.

[0015] Pulmonary fibrosis is a disease of lung tissue characterized by progressive and chronic fibrosis (scarring) which lead to chronic respiratory insufficiency. Different types and causes of pulmonary fibrosis exist but all are characterized by inflammatory cell influx and persistence, activation and proliferation of fibroblasts with collagen deposition in lung tissue. These events seem related to the release of cytokines and chemokines within lung tissue.

[0016] Acute rhinitis is an acute disease that occurs during an infection or irritating event, for example, by pollution, dust, gas or chemicals, of the nose or upper airways. Chronic rhinitis is defined by the presence of a constant chronic runny nose, nasal congestion, sneezing and pruritis. One can also find within the upper airways during acute or chronic rhinitis inflammatory cells with a broad array of chemokines and cytokines. These mediators are thought to play a role in the inflammation, symptoms and mucus production that occur during these diseases.

[0017] Acute sinusitis is an acute, usually infectious disease of the sinuses characterized by nasal congestion, runny, purulent phlegm, headache or sinus pain, with or without fever. Chronic sinusitis is defined by the persistence for more than 6 months of the symptoms of acute sinusitis. One can also find during acute or chronic sinusitis within the upper airways and sinuses inflammatory cells with a broad array of chemokines and cytokines. These mediators are thought to play a role in the inflammation, symptoms and phlegm production that occur during these diseases.

[0018] A neoplasm is an abnormal tissue growth that is uncontrollable and progressive. A malignant neoplasm is often characterized as a cancer. Cancer is the second leading cause of death in humans and is a general term for more than 100 diseases characterized by abnormal proliferation of immortalized cells. One of the mechanisms involved in the persistence and increase in cellular proliferation is the release of growth factors that act through cognate receptors. Amongst these growth factors, GM-CSF has been shown to be an important growth factor for several tumour cells. The chemokine receptor CCR3 was recently characterized in malignant B lymphocytes recovered from patients with chronic lymphocytic leukemia (CLL) and with hairy cell leukemia (HCL), (Trentin et al., 2004, Blood, 104, 502-508). Indeed, the transactivation of Epidermal Growth Factor Receptor (EGFR) through CCR3 chemokine receptor was found to be a critical pathway that elicits MAP kinase activation and cytokine production in bronchial epithelial cells (Adachi et al., 2004, Biochem. Biophys. Res. Commun. 320, 292-396). Inhibition of cancer cell proliferation via blockage of receptors for growth factors and/or chemokines may be important in the therapy of certain cancers.

[0019] Eosinophils are a type of white blood cell. They are granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing course, round granules that are uniform in size and stainable by eosin. Hypereosinophilia is characterized by an increased number of eosinophils, often associated with allergies, asthmas and infections.

[0020] Uses of oligonucleotides directed against specific nucleic acid sequences coding for receptors for inhibition of inflammatory reactions is known. Co-owned International Patent Application Publication Nos. WO 99/66037 and WO 06/045202 describe AONs used for treating and/or preventing asthma, allergy, hypereosinophilia, general inflammation and cancer.

[0021] For potential clinical uses, AONs should exhibit stability against degradation by serum and cellular nucleases, show low non-specific binding to serum and cell proteins, exhibit enhanced recognition of the target mRNA sequence, demonstrate cell-membrane permeability and elicited cellular nucleases when complexed with complementary mRNA. It is well documented that oligonucleotides containing natural sugars (D-ribose and D-2-deoxyribose) and phosphodiester (PO) linkages are rapidly degraded by serum and intracellular nucleases, which limit their utility as effective therapeutic agents. Chemical strategic modifications have been described for oligonucleotides in order to improve their stability and efficacy as therapeutic agents. The main chemical changes included, modification of the sugar moiety, the base moiety, and/or modification or replacement of the internucleotide phosphodiester linkage. To date the most widely studied analogues are the phosphorothioate (PS) oligodeoxynucleotides, in which one of the non-bridging oxygen atoms in the phosphodiester backbone is replaced with a sulfur (Eckstein F., 1985, Ann. Rev. Biochem., 54: 367-402). Several AON generations have been developed and used for in vitro and for in vivo studies (Goodchild J., 2004, Curr. Opin. Mol. Ther., 2004, 6:120-128; Urban E. and R. Noe C R., 2003, Farmaco. 58:243-258).

[0022] It would be desirable to have improved AONs directed against nucleic acid sequences coding for pro-inflammatory receptors for inhibiting these receptors. Such AONs would be useful in the therapy and/or prevention of asthma, allergy, hypereosinophilia, general inflammation and cancer.

SUMMARY OF THE INVENTION

[0023] In accordance with one aspect, there is provided an oligonucleotide directed against a nucleic acid sequence coding for a protein selected from the group consisting of a CCR3 chemokine receptor and a common beta sub-unit of IL-3, IL-5 and GM-CSF receptors, wherein the oligonucleotide is one of (i) having a base sequence corresponding to any one of SEQ ID NOs. 1-698 and (ii) a modified oligonucleotide of any one of SEQ ID NOs. 1-698.

[0024] Preferably, the oligonucleotide has the base sequence corresponding to any one of SEQ ID NOs. 1-698.

[0025] Preferably, at least one adenosine of the oligonucleotide is replaced by a modified nucleotide, preferably a 2-amino-2'-deoxyadenosine (DAP).

[0026] In some embodiments, at least one of the nucleotides of the oligonucleotide is an arabinose modified oligonucleotide, preferably 2'-deoxy-2'-fluoroarabinonucleotide (FANA).

[0027] In some embodiments, the oligonucleotide contains at least one internucleotide linkage selected from the group consisting of phosphodiester, phosphotriester, phosphorothioate, methylphosphonate, boranophosphate and any combination thereof. Preferably, the oligonucleotide is phosphorothioate or phosphodiester oligonucleotide or an oligonucleotide with a combination of phosphorothioate and phosphodiester bonds.

[0028] In accordance with a further aspect, there is provided a pharmaceutical composition comprising at least one of the oligonucleotide described herein and pharmaceutically acceptable carrier.

[0029] In accordance with a further aspect, there is provided a method for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer in a patient comprising administering to said patient a pharmaceutical composition described herein.

[0030] In accordance with a further aspect, there is provided a use of a pharmaceutical composition described herein for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0031] In accordance with a further aspect, there is provided a use of a pharmaceutical composition described herein in the preparation of a medicament for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0032] In accordance with a further aspect, there is provided a method for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression in a patient comprising administering to said patient an oligonucleotide described herein the base sequence of the oligonucleotide having one of SEQ ID NOs. 1-672.

[0033] In accordance with a further aspect, there is provided a use of an oligonucleotide described herein for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 1-672.

[0034] In accordance with a further aspect, there is provided a use of an oligonucleotide described herein in the preparation of a medicament decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression, the sequence of the oligonucleotide having one of SEQ ID NOs. 1-672.

[0035] In accordance with a further aspect, there is provided an oligonucleotide described herein for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 1-672.

[0036] In accordance with a further aspect, there is provided a method for decreasing CCR3 chemokine receptor expression in a patient comprising administering to said patient an oligonucleotide described herein, the base sequence of the oligonucleotide having one of SEQ ID NOs. 673-698.

[0037] In accordance with a further aspect, there is provided a use of an oligonucleotide described herein for decreasing CCR3 chemokine receptor expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 673-698.

[0038] In accordance with a further aspect, there is provided a use of an oligonucleotide described herein in the preparation of a medicament decreasing CCR3 chemokine receptor expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 673-698.

[0039] In accordance with a further aspect, there is provided an oligonucleotide described herein for decreasing CCR3 chemokine receptor expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 673-698.

[0040] In accordance with a further aspect, there is provided a commercial package comprising a pharmaceutical composition described herein together with instructions for its use for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer; for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression in a patient, the base sequence of the oligonucleotide having one of SEQ ID NOs. 1-672; or for decreasing CCR3 chemokine receptor expression in a patient, the base sequence of the oligonucleotide having one of SEQ ID NOs. 673-698.

[0041] In accordance with a further aspect, there is provided a double-stranded siRNA, the two strands comprising one of SEQ ID NOs. 699 and 700; 701 and 702; 703 and 704; 705 and 706; 707 and 708; 709 and 710; 711 and 712; 713 and 714; 715 and 716; 717 and 718; 719 and 720; 721 and 722; 723 and 724; 725 and 726; 727 and 728; 729 and 730; 731 and 732; 733 and 734; 735 and 736; 737 and 738; 739 and 740; 741 and 742; 743 and 744; 745 and 746; 747 and 748; 749 and 750; 752 and 752; 753 and 754; 755 and 756; 757 and 758; 759 and 760; 761 and 762; 763 and 764; 765 and 766; 767 and 768; 769 and 770; 771 and 772; 773 and 774; 775 and 776; 777 and 778; 779 and 780; 781 and 782; 783 and 784; 785 and 786; 787 and 788; 789 and 790; 791 and 792; 793 and 794; 795 and 796; 797 and 798; 799 and 800; 801 and 802; 803 and 804; 805 and 806; 807 and 808; 809 and 810; 811 and 812; 813 and 814; 815 and 816; 817 and 818; 819 and 820; 821 and 822; 823 and 824; 825 and 826; 827 and 828; 829 and 830; 831 and 832; 833 and 834; 835 and 836; 837 and 838; 839 and 840; 841 and 842; 843 and 844; 845 and 846; 847 and 848; 849 and 850; 851 and 852; 853 and 854; 855 and 856; 857 and 858; 859 and 860; 861 and 862; 863 and 864; 865 and 866; 867 and 868; 869 and 870; 871 and 872; 873 and 874; 875 and 876; 877 and 878; 879 and 880; 881 and 882; 883 and 884; 885 and 886; 887 and 888; 889 and 890; 891 and 892; 893 and 894; 895 and 896; 897 and 898; 899 and 900; 901 and 902; 903 and 904; 905 and 906; 907 and 908; 909 and 910; 911 and 912; 913 and 914; 915 and 916; 917 and 918; 919 and 920; 921 and 922; 923 and 924; 925 and 926; 927 and 928; 929 and 930; 931 and 932; 933 and 934; 935 and 936; 937 and 938; 939 and 940; 941 and 942; 943 and 944; 945 and 946; 947 and 948; 949 and 950; 951 and 952; 953 and 954; 955 and 956; 957 and 958; 959 and 960; 961 and 962; 963 and 964; 965 and 966; 967 and 968; 969 and 970; 971 and 972; 973 and 974; 975 and 976; 977 and 978; 979 and 980; 981 and 982; 983 and 984; 985 and 986; 987 and 988; 989 and 990; 991 and 992; 993 and 994; 995 and 996; 997 and 998; 999 and 1000; 1001 and 1002; 1003 and 1004; 1005 and 1006; 1007 and 1008; 1009 and 1010; 1011 and 1012; 1013 and 1014; 1015 and 1016; 1017 and 1018; 1019 and 1020; 1021 and 1022; 1023 and 1024; 1025 and 1026; 1027 and 1028; 1029 and 1030; 1031 and 1032; 1033 and 1034; 1035 and 1036; 1037 and 1038; 1039 and 1040; 1041 and 1042; 1043 and 1044; 1045 and 1046; 1047 and 1048; 1049 and 1050; 1051 and 1052; 1053 and 1054; 1055 and 1056; 1057 and 1058; 1059 and 1060; 1061 and 1062; 1063 and 1064; 1065 and 1066; 1067 and 1068; 1069 and 1070; 1071 and 1072; 1073 and 1074; 1075 and 1076; 1077 and 1078; 1079 and 1080; 1081 and 1082; 1083 and 1084; 1085 and 1086; 1087 and 1088; 1089 and 1090; 1091 and 1092; 1093 and 1094; 1095 and 1096; 1097 and 1098; 1099 and 1100; 1101 and 1102; 1103 and 1104; 1105 and 1106; 1107 and 1108; 1109 and 1110; 1111 and 1112; 1113 and 1114; 1115 and 1116; 1117 and 1118; 1119 and 1120; 1121 and 1122; 1123 and 1124; 1125 and 1126; 1127 and 1128; 1129 and 1130; 1131 and 1132; 1133 and 1134; 1135 and 1136; 1137 and 1138; 1139 and 1140; 1141 and 1142; 1143 and 1144; 1145 and 1146; 1147 and 1148; 1149 and 1150; 1151 and 1152; 1153 and 1154; 1155 and 1156; 1157 and 1158; 1159 and 1160; 1161 and 1162; 1163 and 1164; 1165 and 1166; 1167 and 1168; 1169 and 1170; 1171 and 1172; 1173 and 1174; 1175 and 1176; 1177 and 1178; 1179 and 1180; 1181 and 1182; 1183 and 1184; 1185 and 1186; 1187 and 1188; 1189 and 1190; 1191 and 1192; 1193 and 1194; 1195 and 1196; 1197 and 1198; 1199 and 1200; 1201 and 1202; 1203 and 1204; 1205 and 1206; 1207 and 1208; 1209 and 1210; 1211 and 1212; 1213 and 1214; 1215 and 1216; 1217 and 1218; 1219 and 1220; 1221 and 1222; 1223 and 1224; 1225 and 1226; 1227 and 1228; 1229 and 1230; 1231 and 1232; 1233 and 1234; 1235 and 1236; 1237 and 1238; 1239 and 1240; 1241 and 1242; 1243 and 1244; 1245 and 1246; 1247 and 1248; 1249 and 1250; 1251 and 1252; 1253 and 1254; 1255 and 1256; 1257 and 1258; 1259 and 1260; 1261 and 1262; 1263 and 1264; 1265 and 1266; 1267 and 1268; 1269 and 1270; 1271 and 1272; 1273 and 1274; 1275 and 1276; 1277 and 1278; 1279 and 1280; 1281 and 1282; 1283 and 1284; 1285 and 1286; 1287 and 1288; 1289 and 1290; 1291 and 1292; 1293 and 1294; 1295 and 1296; 1297 and 1298; 1299 and 1300; 1301 and 1302; 1303 and 1304; 1305 and 1306; 1307 and 1308; 1309 and 1310; 1311 and 1312; 1313 and 1314; 1315 and 1316; 1317 and 1318; 1319 and 1320; 1321 and 1322; 1323 and 1324; 1325 and 1326; 1327 and 1328; 1329 and 1330; 1331 and 1332; 1333 and 1334; 1335 and 1336; 1337 and 1338; 1339 and 1340; 1341 and 1342; 1343 and 1344; 1345 and 1346; 1347 and 1348; 1349 and 1350; 1351 and 1352; 1353 and 1354; 1355 and 1356; 1357 and 1358; 1359 and 1360; 1361 and 1362; 1363 and 1364; 1365 and 1366; 1367 and 1368; 1369 and 1370; 1371 and 1372; 1373 and 134; 1375 and 1376; 1377 and 1378; 1379 and 1380; 1381 and 1382; 1383 and 1384; 1385 and 1386; 1387 and 1388; 1389 and 1390; 1391 and 1392; 1393 and 1394; 1395 and 1396; 1397 and 1398; 1399 and 1400; 1401 and 1402; 1403 and 1404; 1405 and 1406; 1407 and 1408; 1409 and 1410; 1411 and 1412; 1413 and 1414; 1415 and 1416; 1417 and 1418; 1419 and 1420; 1421 and 1422; 1423 and 1424; 1425 and 1426; 1427 and 1428; 1429 and 1430; 1431 and 1432; 1433 and 1434; 1435 and 1436; 1437 and 1438; 1439 and 1440; 1441 and 1442; 1443 and 1444; 1445 and 1446; 1447 and 1448; 1449 and 1450; 1451 and 1452; 1453 and 1454; 1455 and 1456; 1457 and 1458; 1459 and 1460; 1461 and 1462; 1463 and 1464; 1465 and 1466; 1467 and 1468; 1469 and 1470; 1471 and 1472; 1473 and 1474; 1475 and 1476; 1477 and 1478; 1479 and 1480; 1481 and 1482; 1483 and 1484; 1485 and 1486; 1487 and 1488; 1489 and 1490; 1491 and 1492; 1493 and 1494; 1495 and 1496; 1497 and 1498; 1499 and 1500; 1501 and 1502; 1503 and 1504; 1505 and 1506; 1507 and 1508; 1509 and 1510; 1511 and 1512; 1513 and 1514; 1515 and 1516; 1517 and 1518; 1519 and 1520; 1521 and 1522; 1523 and 1524; 1525 and 1526; 1527 and 1528; 1529 and 1530; 1531 and 1532; 1533 and 1534; 1535 and 1536; 1537 and 1538; 1539 and 1540; 1541 and 1542; 1543 and 1544; 1545 and 1546; 1547 and 1548; 1549 and 1550; 1551 and 1552; 1553 and 1554; 1555 and 1556; 1557 and 1558; 1559 and 1560; 1561 and 1562; 1563 and 1564; 1565 and 1566; 1567 and 1568; 1569 and 1570; and 1571 and 1572, preferably for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression.

[0042] In accordance with a further aspect, there is provided a double-stranded siRNA, the two strands comprising one of SEQ ID NOs. 1573 and 1574; 1575 and 1576; and 1577 and 1578, preferably for decreasing CCR3 chemokine receptor expression.

[0043] In accordance with a further aspect, there is provided the siRNA described herein for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0044] In accordance with a further aspect, there is provided the siRNA described herein, wherein at least one nucleotide of the siRNA is FANA.

[0045] In accordance with a further aspect, there is provided the siRNA described herein wherein at least one adenosine nucleotide of the siRNA is substituted with DAP or an analog thereof.

[0046] In accordance with a further aspect, there is provided a method for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression in a patient comprising administering the siRNA described herein.

[0047] In accordance with a further aspect, there is provided a method for decreasing CCR3 chemokine receptor expression in a patient comprising administering the siRNA described herein.

[0048] In accordance with a further aspect, there is provided a method for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer in a patient comprising administering the siRNA described herein.

[0049] In accordance with a further aspect, there is provided use of the siRNA described herein for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression or CCR3 chemokine receptor expression or for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0050] In accordance with a further aspect, there is provided a use of the siRNA described herein in the preparation of a medicament for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression; or for decreasing CCR3 chemokine receptor expression; or for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0051] In accordance with a further aspect, there is provided a double-stranded or single-stranded miRNA comprising a pair of oligonucleotides or single oligonucleotide selected from the group consisting of SEQ ID NOs: 1634 and 1635; 1636 and 1637; 1638 and 1639; 1640 and 1641; 1642 and 1643; 1644 and 1645; 1646 and 1647; 1648; 1649 and 1650; 1651 and 1652; 1653 and 1654; 1655 and 1656; 1657 and 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666 and 1667; 1668 and 1669; 1670 and 1671; 1672 and 1673; 1674 and 1675; 1676 and 1677; 1678; 1679 and 1680; 1681 and 1682; 1683 and 1684; 1685 and 1686; 1687 and 1688; 1689 and 1690; 1691 and 1692; 1693; 1694; 1695 and 1696; 1697; 1698; 1699 and 1700; 1701; 1702 and 1703; 1704; 1705; 1706; 1707; 1708; 1709; 1710; 1711; 1712 and 1713; 1714 and 1715; 1716; 1717 and 1718; 1719; 1720 and 1721; 1722 and 1723; 1724; 1725 and 1726; 1727; 1728; 1729 and 1730; 1731 and 1732; 1733 and 1734; 1735; 1736; 1737; 1738 and 1739; 1740 and 1741; 1742; 1743 and 1744; 1745; 1746 and 1747; 1748 and 1749; 1750 and 1751; 1752; 1753; 1754; 1755; 1756; 1757; 1758; 1759; 1760; 1761 and 1762; 1763; 1764 and 1765; 1766; 1767 and 1768; 1769; 1770; 1771; 1772; 1773; 1774 and 1775; 1776; 1777; and 1778, preferably for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression.

[0052] In accordance with a further aspect, there is provided the miRNA described herein, wherein at least one nucleotide of the miRNA is FANA.

[0053] In accordance with a further aspect, there is provided the miRNA described herein wherein at least one adenosine nucleotide of the miRNA is substituted with DAP or an analog thereof.

[0054] In accordance with a further aspect, there is provided a method for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression in a patient comprising administering the miRNA described herein.

[0055] In accordance with a further aspect, there is provided a method for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer in a patient comprising administering the miRNA described herein.

[0056] In accordance with a further aspect, there is provided use of the miRNA described herein for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression or for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0057] In accordance with a further aspect, there is provided a use of the miRNA described herein in the preparation of a medicament for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression; or for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0058] In accordance with a further aspect, there is provided an AON capable of hybridizing under highly stringent conditions with a nucleic acid sequence coding for a protein selected from the group consisting of a CCR3 chemokine receptor and a common beta sub-unit of IL-3, IL-5 and GM-CSF receptors, wherein at least one nucleotide in the oligonucleotide is a 2'-deoxy-2'-fluoroarabinonucleotide (FANA).

[0059] In accordance with a further aspect, there is provided an AON capable of hybridizing under highly stringent conditions with a nucleic acid sequence coding for the common beta sub-unit of IL-3, IL-5 and GM-CSF receptors, wherein at least one adenosine nucleotide in the oligonucleotide is substituted with 2-amino-2'-deoxyadenosine (DAP).

[0060] In accordance with a further aspect, there is provided a method of improving the therapeutic efficacy to toxicity ratio of an oligonucleotide administered to a mammal comprising: (a) identifying the oligonucleotide as being intended for administration to the lung and where lowered toxicity is desired; and (b) replacing at least one non-FANA nucleotide with a corresponding FANA nucleotide and/or replacing one adenosine with 2-amino-2'-deoxyadenosine. Preferably, the administration of the resulting oligonucleotide to the mammal results in enhanced potency and/or reduced toxicity compared to administration of an unmodified oligonucleotide.

[0061] In accordance with a further aspect, there is provided an AON capable of hybridizing under highly stringent conditions with a nucleic acid sequence coding for a protein selected from the group consisting of a CCR3 chemokine receptor and a common beta sub-unit of IL-3, IL-5 and GM-CSF receptors, wherein the internucleotide linkages of the oligonucleotide comprise both phosphodiester and phosphorothioate linkages.

BRIEF DESCRIPTION OF THE DRAWINGS

[0062] FIG. 1 illustrates the efficacy of AON sequences at reducing the β-chain mRNA expression. FIG. 1a shows the efficacy of AON sequences TOP057 (SEQ ID No: 8) to TOP073 (SEQ ID No: 24). TF-1 cells (668 nM) or 293-βc-GFP cells (267 nM) were transfected for 24 hours and β-chain mRNA expression level was quantified using Quantigene. Results are expressed as mean percentage of β-chain mRNA inhibition (normalized to β2M)±SEM (compilation from two experiments in TF-1 cell line and two experiments in 293-CCR3-GFP cell line) compared to untransfected control cells. The specific activities of AON sequences TOP057 (SEQ ID No: 8), TOP062 (SEQ ID No: 13) and TOP063 (SEQ ID No: 14) were compared to corresponding sense control sequences (TOP057s (SEQ ID No: 1779), TOP062s (SEQ ID No: 1780) and TOP063s (SEQ ID No: 1781)) in FIG. 1b 293-βc-GFP cells (267 nM) and; FIG. 1c TF-1 cells (500 nM). Cells were transfected for 24 hours and β-chain mRNA expression levels were quantified using Quantigene. Results are expressed as mean normalized ratio β-chain/β2M±SEM. The percentage inhibition of β-chain mRNA relative to the corresponding sense control AON is indicated. Statistical analysis was performed using the ANOVA test (Dunnett's post test, n=3, **p<0.01).

[0063] FIG. 2 illustrates the efficacy of AON sequences at reducing the CCR3 mRNA expression. FIG. 2a describes the efficacy of AON sequences TOP020 (SEQ ID No: 673) to TOP045 (SEQ ID No: 698). TF-1 cells (668 nM) or 293-CCR3-GFP cells (267 nM) were transfected with indicated AONs. Twenty-four hours post-transfection CCR3 mRNA expression levels were quantified using Quantigene. Results are provided as mean percentage of CCR3 mRNA expression inhibition ±SEM (compilation from 2 experiments in TF-1 and 4 experiments in 293-CCR3-GFP cells) compared to non-transfected control cells. FIG. 2b illustrates the specific activities of AON sequences TOP030 (SEQ ID No: 683) and TOP031 (SEQ ID No: 684) compared to corresponding sense control sequences (TOP030s (SEQ ID No: 1782) and TOP031s (SEQ ID No: 1783)) in 293-CCR3-GFP cells (267 nM). FIG. 2c illustrates similar results obtained for TF-1 cells (668 nM). Cells were transfected and 24 hours post-transfection CCR3 mRNA expression levels were quantified using Quantigene. Results are expressed as mean±SEM normalized ratio CCR3/β2M±SEM. The percentage inhibition of CCR3 mRNA expression relative to the corresponding sense control AON is indicated. Statistical analysis was performed using the ANOVA test (Dunnett's post test, n=3, **p<0.01).

[0064] FIG. 3 illustrates the efficacy of siRNA sequences at reducing β-chain mRNA expression levels. FIG. 3a illustrates the efficacy of siRNA sequences at reducing β-chain mRNA expression in 293-βc-GET cells 24 hours post-transfection at doses of 0.04, 0.12 and 0.24 μM. FIGS. 3b and 3c compare the efficacy of β-chain AON (TOP062 (SEQ ID No: 13)) and siRNA sequences at reducing β-chain mRNA expression levels in TF-1 cells. For the dose-response experiment, cells were transfected with the indicated AON or siRNA at doses of 0.25 μM, 0.5 μM and 1 μM (FIG. 3b). For the time-course study, cells were transfected with 1 μM of the indicated AON or siRNA and β-chain mRNA expression quantification was performed 24, 48 or 72 hours post-transfection using the Quantigene assay (FIG. 3c). Results are expressed as the mean ratios (±SEM) of β-chain relative luminescence units (RLU) normalized to β2M control gene RLU. Statistical analysis was performed using one-way ANOVA followed by a Dunnett post-test with TOP062 (SEQ ID No: 13) as control reference (*p<0.05, **p<0.01, n=3 replicates per condition).

[0065] FIG. 4 illustrates the efficacy of siRNA sequences at reducing CCR3 mRNA expression levels. FIG. 4a illustrates the efficacy of siRNA sequences at reducing CCR3 mRNA expression levels following transfection in 293-CCR3-GFP cells. Cells were transfected with siRNAs at doses ranging from 0.04 μM to 0.24 uM and CCR3 mRNA expression determined 24 hours post-transfection. FIG. 4b compares the efficacy of indicated AON and siRNA sequences at reducing CCR3 mRNA expression levels in 293-CCR3-GFP cells. 293-CCR3-GFP cells were transfected with indicated AON or siRNA at a concentration of 300 nM, and CCR3 mRNA expression quantification was performed 24, 48 or 72 hours post-transfection. Total RNA was extracted from transfected cells, purified, and subjected to CCR3 mRNA quantification using the Quantigene assay. Results are expressed as the mean ratios (±SEM) of CCR3 relative luminescence units (RLU) normalized to β2M control gene RLU. Statistical analysis was performed using one-way ANOVA followed by a Dunnett post-test with TOP030 (SEQ ID No: 683) as control reference (*p<0.05, **p<0.01, n=3 replicates per condition).

[0066] FIG. 5 illustrates the efficacy of selected AON sequences at reducing β-chain or CCR3 protein expression. Cells were transfected with indicated AONs or their control sense sequence (267 nM of AON was transfected into 293-βc-GFP and 293-CCR3-GFP cells; 667 nM of AON was transfected into TF-1 cells) and protein levels were analyzed by flow cytometry 24 hours post-transfection. In FIGS. 5a and 5c, results are expressed as the mean percentage±SEM of 293-βc-GFP and 293-CCR3-GFP cells positive for the expression of βc-GFP and CCR3-GFP proteins, respectively. In FIGS. 5b and 5d, results are expressed as the average mean fluorescence intensity (MFI)±SEM of β-chain and CCR3 protein expression, respectively, in TF-1 cells. The percentage of inhibition of target protein expression relative to the corresponding sense control AON is indicated. Statistical analysis was performed using the unpaired t test, with n=3 and **p<0.01, ***p<0.001.

[0067] FIG. 6 illustrates the efficacy of FANA-containing TOP062 (SEQ ID No: 13) and TOP030 (SEQ ID No: 683) AONs at reducing α-chain (293-βc-GFP cells) and CCR3 (TF-1 cells) protein levels, respectively. 293-βc-GFP cells were transfected with 200 nM AON while TF-1 cells were transfected with 668 nM AON. Protein expression levels were measured by flow cytometry 24 hours post-transfection. Results are expressed as the main percentage of cells positive for β-chain (FIG. 6a) and CCR3 (FIG. 6b) protein expression ±SEM. Statistical analysis was performed using the ANOVA test (Dunnett's post test), with n=3 or 4, *p<0.05 and **p<0.01.

[0068] FIG. 7 illustrates the increased serum stability of FANA-containing TOP062 (SEQ ID No: 13) (FIG. 7a) and TOP030 (SEQ ID No: 683) (FIG. 7b) AONs. AONs were incubated at 37° C. in DMEM containing 50% fetal bovine serum. Samples were collected at different time points and analyzed using anion exchange HPLC. The percentage of intact AON remaining was determined by comparing the corresponding peak area to the value of the peak area at time point 0 hours set at 100%.

[0069] FIG. 8 illustrates the cross-target effect of TOP062-F8 (SEQ ID No: 1588) (β-chain AON) on CCR3 expression and TOP030-F2 (SEQ ID No: 1600) (CCR3 AON) on β-chain expression. TF-1 cells were transfected with either AON singly at a concentration of 167 nM or 668 nM. Twenty-four hours post-transfection cells were analyzed for mRNA and protein expression levels of CCR3 (FIGS. 8a and 8b) and β-chain (FIGS. 8c and 8d). The mRNA expression level results are given as the average ±SEM of normalized ratio CCR3 or β-chain/β2M while protein expression results are given as the mean percentage ±SEM of cells expressing CCR3 or β-chain protein.

[0070] FIG. 9 illustrates the cross target effect of TOP62-F8 (SEQ ID No: 1588) and TOP30-F2 (SEQ ID No: 1600) (TPI2200) AONs on CCR3 (FIG. 9a) and β-chain (FIG. 9b) protein expression. TF-1 cells were transfected with indicated AON sequences at a concentration of 668 nM. Twenty-four hours post-transfection protein expression levels were measured by flow cytometry. Results were expressed as the mean fluorescence intensity (MFI±SEM).

[0071] FIG. 10 illustrates the efficacy of TOP062-F8 (SEQ ID No: 1588) and TOP030-F2 (SEQ ID No: 1600) alone or in combination on inhibition of CCR3 and β-chain mRNA and protein expression. TF-1 cells were transfected with one AON alone (334 nM or 668 nM) or in combination (334 nM each AON). Twenty-four hours post-transection mRNA and protein levels of CCR3 (FIGS. 10a and 10b) and β-chain (FIGS. 10c and 10d) were quantified. mRNA expression results are given as the average ±SEM normalized ratio CCR3 or β-chain/β2M while protein expression results are given as the mean percentage ±SEM of cells expressing CCR3 or β-chain protein. The percentage of expression inhibition relative to untransfected control cells is indicated. Statistical analysis was performed using unpaired t test with n=3, *p<0.05 and **p<0.01.

[0072] FIG. 11 illustrates the activity of FANA-containing TOP007 (SEQ ID No: 1628) AON at reducing the rat CCR3 mRNA expression levels. NIH-3T3 cells were co-transfected with 0.2 μg of an expression plasmid containing the rat CCR3 cDNA (pCMVscript rat CCR3) and 0.2 μg of the indicated AON. Twenty-four hours post-transfection CCR3 mRNA expression levels were quantified. CCR3 mRNA expression levels post-transfection were normalized against the expression levels of a control plasmid (pGL2-Luciferase). The results are expressed as the percentage of CCR3 mRNA expression inhibition relative to the corresponding mRNA expression inhibition levels in cells expressing a mismatch control AON.

[0073] FIG. 12 illustrates a comparison of the effect of combinations of AONs targeting the rat β-chain (TOP006 (SEQ ID No: 1626)) and CCR3 (TOP007 (SEQ ID No: 1628)) to combinations of FANA-modified versions of the same AONs (TOP006-F2 (SEQ ID No: 1627) and TOP007-F8 (SEQ ID No: 1629), respectively) on allergen-induced eosinophil influx into the lungs of sensitized BN rats. Fourteen days following OVA-sensitization, rats were either unchallenged or treated with a single intra-tracheal administration of vehicle or 25 μg of each combination of AON (total of 50 μg per animal) as indicated prior to the OVA challenge. Rats were sacrificed 15 hours after OVA challenge, and differential cell counts from the BAL fluid were performed. Data represent mean total cell number +/-SEM from 3 separate experiments. One-way ANOVA followed by Dunnett's multiple comparison test (versus treated with vehicle and OVA challenged) (*p<0.05; **p<0.01); n=14 to 23 rats per group.

[0074] FIG. 13 illustrates a comparison of the effects of FANA modified AONs (TPI 1100) to non-FANA modified AONs (TPI ASM8) on the percentage incidence of foamy macrophages in the lung of rodents (mice and rats) and of monkeys following chronic dosing.

[0075] FIG. 14 illustrates a comparison of the efficacy of select AONs targeting the β-chain (TOP062 (SEQ ID No: 13), TOP057 (SEQ ID No: 8), TOP073 (SEQ ID No: 24) and TOP077 (SEQ ID No: 28)) to the efficacy of DAP-modified versions of the same AON (TOP062-DAP (SEQ ID No: 1621), TOP057-DAP (SEQ ID No: 1622), TOP073-DAP (SEQ ID No: 1623) and TOP077-DAP (SEQ ID No: 1624), respectively) at reducing β-chain mRNA expression levels determined using Quantigene. 293-βc-GFP cells were transfected with 267 nM AON and 24 hours post-transfection RNA was extracted and β-chain mRNA expression levels quantified. mRNA expression levels are given as the average ±SD normalized ratio β-chain/β2M. Statistical analyses were carried out using a One Way ANOVA (Dunnett) against the negative control oligonucleotide TOP4005 (SEQ ID No: 1784);** p<0.01, n=3.

[0076] FIG. 15 illustrates the efficacy of selected miRNA mimic sequences TOP5120 (SEQ ID NOs: 1636 and 1637), TOP5121 (SEQ ID NOs: 1638 and 1639), TOP5122 (SEQ ID NOs: 1640 and 1641), TOP05123 (SEQ ID NOs: 1642 and 1643) and TOP5124 (SEQ ID NOs: 1644 and 1645) at reducing β-chain mRNA and protein expression levels. TF-1 cells were transfected with 0.5 or 1 μM miRNA. Twenty-four hours post-transfection expression levels were determined. FIGS. 15a and 15b illustrate a comparison of the efficacy of miRNA mimic sequences at reducing β-chain mRNA expression and protein expression levels, respectively. mRNA expression level results are given as the average ±SD normalized ratio β-chain/β2M (FIG. 15a) while protein expression results are given as the mean percentage ±SD of cells expressing β-chain protein (FIG. 15b). Statistical analyses were carried out using a One Way ANOVA (Dunnett) against the untransfected cells (Control NT); ** p<0.01, n=3-6.

BRIEF DESCRIPTION OF THE TABLES

[0077] Table 1a identifies AON sequences with specificity for the common beta subunit (β-chain) of IL-3, IL-5 and GM-CSF receptors in accordance with the present invention.

[0078] Table 1b identifies AON sequences with specificity against the CCR3 chemokine receptor in accordance with the present invention.

[0079] Table 2a identifies siRNA sequences designed against the common beta subunit (β-chain) of IL-3, IL-5 and GM-CSF receptors in accordance with the present invention.

[0080] Table 2b identifies siRNA sequences designed against CCR3 chemokine receptor in accordance with the present invention.

[0081] Table 3a identifies AON sequences containing FANA modification with specificity against the common beta subunit (β-chain) of IL-3, IL-5 and GM-CSF receptors in accordance with the present invention.

[0082] Table 3b identifies AON sequences containing FANA modification with specificity against the CCR3 chemokine receptor in accordance with the present invention.

[0083] Table 3c identifies AON sequences containing DAP modification with specificity against the common beta subunit (β-chain) of IL-3, IL-5 and GM-CSF receptors in accordance with the present invention.

[0084] Table 4 identifies AON sequences with specificity against the rat common beta subunit (β-chain) of IL-3, IL-5 and GM-CSF receptors and the rat CCR3 chemokine receptor in accordance with the present invention.

[0085] Table 5 identifies primary treatment-related histopathologic changes in the lungs of monkeys treated with 2'F-ANA modified AONs (TPI 1100) or non 2'F-ANA modified AONs (TPI ASM8).

[0086] Table 6 identifies AON sequences TPI 1100 and TPI ASM8.

[0087] Table 7 identifies miRNA mimic sequences with specificity against the common beta subunit (β-chain) of IL-3, IL-5 and GM-CSF receptors in accordance with the present invention.

[0088] Table 8 identifies sense oligonucleotide sequences TOP057s (SEQ ID NO: 1779), TOP062s (SEQ ID NO: 1780), TOP063s (SEQ ID NO: 1781), TOP030s (SEQ ID NO: 1782), and TOP031s (SEQ ID NO: 1783), as well as nonspecific antisense oligonucleotide sequence TOP4005 (SEQ ID NO: 1784), each of which is used as a control in an experiment-dependent manner.

DETAILED DESCRIPTION OF THE INVENTION

[0089] Several inflammatory mediators play a role in the appearance and perpetuation of inflammation in the airways of patients with asthma. Some mediators attract the inflammatory cells into the airways through chemotaxis of eosinophils. Many of these chemokines act mostly in asthmatic or allergic inflammation through the CCR3 receptor. Other mediators cause the priming and increased survival of inflammatory cells in the airways or skin such as IL-3, IL-5, and GM-CSF. An improvement in asthma has been shown when there is a decrease in these inflammatory mediators in the airways.

[0090] Furthermore, cancer, characterized by abnormal proliferation of immortalized cells, can be caused by the release of inflammatory mediators and/or growth factors that act through receptors and lead to cellular proliferation. Amongst these, GM-CSF has been shown to be an important growth factor for several tumour cells. The chemokine receptor CCR3 was characterized in malignant B lymphocytes recovered from patients with chronic lymphocytic leukemia (CLL) and with hairy cell leukemia (HCL), (Trentin et al., 2004, Blood, 104, 502-508). Indeed, the transactivation of EGFR through CCR3 was found to be a critical pathway that elicits MAP kinase activation and cytokine production in bronchial epithelial cells (Adachi et al., 2004, Biochem. Biophys. Res. Commun. 320, 292-396). The inhibition of proliferation and metastasis of cancerous cells by blocking the receptors for growth factors or the chemokine receptor CCR3 could be important in the therapy of certain cancers.

[0091] In accordance with one aspect, there is provided an oligonucleotide directed against a nucleic acid sequence coding for a protein selected from the group consisting of a CCR3 chemokine receptor and a common beta sub-unit of IL-3, IL-5 and GM-CSF receptors, wherein the oligonucleotide is one of (i) having a base sequence corresponding to any one of SEQ ID NOs. 1-698 and (ii) a modified oligonucleotide of any one of SEQ ID NOs. 1-698.

[0092] Preferably, the oligonucleotide has the base sequence corresponding to any one of SEQ ID NOs. 1-698 and is preferably the oligonucleotide of any one of SEQ ID NOs. 1-698.

[0093] Preferably, at least one adenosine is substituted with a nucleotide substitute selected from the group consisting of 2-amino-2'-deoxyadenosine and analogs. Preferred 2-amino-2'-deoxyadenosine analogs include 2,6-diamino-deoxyadenosine hemisulfate, 2-amino-9-(B-D-2'-deoxyribofuranosyl)adenosine, 7-deaza-2'-deoxyadenosine, N6-methyl-2'-deoxyribofuranosyl adenosine, 2-aminoadenosine/2,6-diaminopurine riboside, salts and functional derivatives thereof.

[0094] Preferably, at least one of the nucleotides of the oligonucleotide is an arabinose modified nucleotide, preferably having a 2' substituent selected from the group consisting of fluorine, hydroxyl, amino, azido, alkyl, alkoxy, and alkoxyalkyl groups. Preferably, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, butyl, and functionalized alkyl groups, the alkoxy group is selected from the group consisting of methoxy, ethoxy, proproxy and functionalized alkoxy groups and the alkoxyalkyl group is selected from the group consisting of methoxyethyl, and ethoxyethyl.

[0095] Preferably, the functionalized alkyl group is selected from the group consisting of ethylamino, propylamino and butylamino group and the functionalized alkoxy group is selected from the group consisting of --O(CH₂)_q--R, where q=2-4 and --R is a --NH₂, --OCH₃, or --OCH₂CH₃ group.

[0096] Preferably the arabinose modified nucleotide is 2'-deoxy-2'-fluoroarabinonucleotide (FANA).

[0097] In some embodiments, the at least one arabinose modified nucleotide is at the 5' end or the 3' end of the oligonucleotide; or at both ends.

[0098] In some embodiments, the oligonucleotide has between 1-7 arabinose modified nucleotides independently at the 5' end and 3' end of the oligonucleotide. Preferably, there is between 1-6, 1-5, 1-4, or 1-3 arabinose modified nucleotides independently at the 5' end and 3' end of the oligonucleotide.

[0099] In some embodiments, the oligonucleotide contains at least one internucleotide linkage selected from the group consisting of phosphodiester, phosphotriester, phosphorothioate, methylphosphonate, boranophosphate and any combination thereof. Preferably, the oligonucleotide is phosphorothioate or phosphodiester oligonucleotide or an oligonucleotide with a combination of phosphorothioate and phosphodiester bonds.

[0100] In accordance with a further aspect, there is provided a pharmaceutical composition comprising at least one of the oligonucleotides described herein and a pharmaceutically acceptable carrier.

[0101] In accordance with a further aspect, there is provided a method for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer in a patient comprising administering to said patient a pharmaceutical composition described herein.

[0102] In accordance with a further aspect, there is provided a use of a pharmaceutical composition described herein for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0103] In accordance with a further aspect, there is provided a use of a pharmaceutical composition described herein in the preparation of a medicament for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0104] In accordance with a further aspect, there is provided a method for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression in a patient comprising administering to said patient an oligonucleotide described herein, the base sequence of the oligonucleotide having one of SEQ ID NOs. 1-672.

[0105] In accordance with a further aspect, there is provided a use of an oligonucleotide described herein for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 1-672.

[0106] In accordance with a further aspect, there is provided a use of an oligonucleotide described herein in the preparation of a medicament decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 1-672.

[0107] In accordance with a further aspect, there is provided an oligonucleotide described herein for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 1-672.

[0108] In accordance with a further aspect, there is provided a method for decreasing CCR3 chemokine receptor expression in a patient comprising administering to said patient an oligonucleotide described herein, the base sequence of the oligonucleotide having one of SEQ ID NOs. 673-698.

[0109] In accordance with a further aspect, there is provided a use of an oligonucleotide described herein for decreasing CCR3 chemokine receptor expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 673-698.

[0110] In accordance with a further aspect, there is provided a use of an oligonucleotide described herein in the preparation of a medicament decreasing CCR3 chemokine receptor expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 673-698.

[0111] In accordance with a further aspect, there is provided an oligonucleotide described herein for decreasing CCR3 chemokine receptor expression, the base sequence of the oligonucleotide having one of SEQ ID NOs. 673-698.

[0112] In accordance with a further aspect, there is provided a commercial package comprising a pharmaceutical composition described herein together with instructions for its use for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer; for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression in a patient, the base sequence of the oligonucleotide having one of SEQ ID NOs: 1-672; or for decreasing CCR3 chemokine receptor expression in a patient, the base sequence of the oligonucleotide having one of SEQ ID NOs: 673-698.

[0113] In accordance with a further aspect, there is provided a double-stranded siRNA, the two strands comprising one of SEQ ID NOs: 699 and 700; 701 and 702; 703 and 704; 705 and 706; 707 and 708; 709 and 710; 711 and 712; 713 and 714; 715 and 716; 717 and 718; 719 and 720; 721 and 722; 723 and 724; 725 and 726; 727 and 728; 729 and 730; 731 and 732; 733 and 734; 735 and 736; 737 and 738; 739 and 740; 741 and 742; 743 and 744; 745 and 746; 747 and 748; 749 and 750; 752 and 752; 753 and 754; 755 and 756; 757 and 758; 759 and 760; 761 and 762; 763 and 764; 765 and 766; 767 and 768; 769 and 770; 771 and 772; 773 and 774; 775 and 776; 777 and 778; 779 and 780; 781 and 782; 783 and 784; 785 and 786; 787 and 788; 789 and 790; 791 and 792; 793 and 794; 795 and 796; 797 and 798; 799 and 800; 801 and 802; 803 and 804; 805 and 806; 807 and 808; 809 and 810; 811 and 812; 813 and 814; 815 and 816; 817 and 818; 819 and 820; 821 and 822; 823 and 824; 825 and 826; 827 and 828; 829 and 830; 831 and 832; 833 and 834; 835 and 836; 837 and 838; 839 and 840; 841 and 842; 843 and 844; 845 and 846; 847 and 848; 849 and 850; 851 and 852; 853 and 854; 855 and 856; 857 and 858; 859 and 860; 861 and 862; 863 and 864; 865 and 866; 867 and 868; 869 and 870; 871 and 872; 873 and 874; 875 and 876; 877 and 878; 879 and 880; 881 and 882; 883 and 884; 885 and 886; 887 and 888; 889 and 890; 891 and 892; 893 and 894; 895 and 896; 897 and 898; 899 and 900; 901 and 902; 903 and 904; 905 and 906; 907 and 908; 909 and 910; 911 and 912; 913 and 914; 915 and 916; 917 and 918; 919 and 920; 921 and 922; 923 and 924; 925 and 926; 927 and 928; 929 and 930; 931 and 932; 933 and 934; 935 and 936; 937 and 938; 939 and 940; 941 and 942; 943 and 944; 945 and 946; 947 and 948; 949 and 950; 951 and 952; 953 and 954; 955 and 956; 957 and 958; 959 and 960; 961 and 962; 963 and 964; 965 and 966; 967 and 968; 969 and 970; 971 and 972; 973 and 974; 975 and 976; 977 and 978; 979 and 980; 981 and 982; 983 and 984; 985 and 986; 987 and 988; 989 and 990; 991 and 992; 993 and 994; 995 and 996; 997 and 998; 999 and 1000; 1001 and 1002; 1003 and 1004; 1005 and 1006; 1007 and 1008; 1009 and 1010; 1011 and 1012; 1013 and 1014; 1015 and 1016; 1017 and 1018; 1019 and 1020; 1021 and 1022; 1023 and 1024; 1025 and 1026; 1027 and 1028; 1029 and 1030; 1031 and 1032; 1033 and 1034; 1035 and 1036; 1037 and 1038; 1039 and 1040; 1041 and 1042; 1043 and 1044; 1045 and 1046; 1047 and 1048; 1049 and 1050; 1051 and 1052; 1053 and 1054; 1055 and 1056; 1057 and 1058; 1059 and 1060; 1061 and 1062; 1063 and 1064; 1065 and 1066; 1067 and 1068; 1069 and 1070; 1071 and 1072; 1073 and 1074; 1075 and 1076; 1077 and 1078; 1079 and 1080; 1081 and 1082; 1083 and 1084; 1085 and 1086; 1087 and 1088; 1089 and 1090; 1091 and 1092; 1093 and 1094; 1095 and 1096; 1097 and 1098; 1099 and 1100; 1101 and 1102; 1103 and 1104; 1105 and 1106; 1107 and 1108; 1109 and 1110; 1111 and 1112; 1113 and 1114; 1115 and 1116; 1117 and 1118; 1119 and 1120; 1121 and 1122; 1123 and 1124; 1125 and 1126; 1127 and 1128; 1129 and 1130; 1131 and 1132; 1133 and 1134; 1135 and 1136; 1137 and 1138; 1139 and 1140; 1141 and 1142; 1143 and 1144; 1145 and 1146; 1147 and 1148; 1149 and 1150; 1151 and 1152; 1153 and 1154; 1155 and 1156; 1157 and 1158; 1159 and 1160; 1161 and 1162; 1163 and 1164; 1165 and 1166; 1167 and 1168; 1169 and 1170; 1171 and 1172; 1173 and 1174; 1175 and 1176; 1177 and 1178; 1179 and 1180; 1181 and 1182; 1183 and 1184; 1185 and 1186; 1187 and 1188; 1189 and 1190; 1191 and 1192; 1193 and 1194; 1195 and 1196; 1197 and 1198; 1199 and 1200; 1201 and 1202; 1203 and 1204; 1205 and 1206; 1207 and 1208; 1209 and 1210; 1211 and 1212; 1213 and 1214; 1215 and 1216; 1217 and 1218; 1219 and 1220; 1221 and 1222; 1223 and 1224; 1225 and 1226; 1227 and 1228; 1229 and 1230; 1231 and 1232; 1233 and 1234; 1235 and 1236; 1237 and 1238; 1239 and 1240; 1241 and 1242; 1243 and 1244; 1245 and 1246; 1247 and 1248; 1249 and 1250; 1251 and 1252; 1253 and 1254; 1255 and 1256; 1257 and 1258; 1259 and 1260; 1261 and 1262; 1263 and 1264; 1265 and 1266; 1267 and 1268; 1269 and 1270; 1271 and 1272; 1273 and 1274; 1275 and 1276; 1277 and 1278; 1279 and 1280; 1281 and 1282; 1283 and 1284; 1285 and 1286; 1287 and 1288; 1289 and 1290; 1291 and 1292; 1293 and 1294; 1295 and 1296; 1297 and 1298; 1299 and 1300; 1301 and 1302; 1303 and 1304; 1305 and 1306; 1307 and 1308; 1309 and 1310; 1311 and 1312; 1313 and 1314; 1315 and 1316; 1317 and 1318; 1319 and 1320; 1321 and 1322; 1323 and 1324; 1325 and 1326; 1327 and 1328; 1329 and 1330; 1331 and 1332; 1333 and 1334; 1335 and 1336; 1337 and 1338; 1339 and 1340; 1341 and 1342; 1343 and 1344; 1345 and 1346; 1347 and 1348; 1349 and 1350; 1351 and 1352; 1353 and 1354; 1355 and 1356; 1357 and 1358; 1359 and 1360; 1361 and 1362; 1363 and 1364; 1365 and 1366; 1367 and 1368; 1369 and 1370; 1371 and 1372; 1373 and 134; 1375 and 1376; 1377 and 1378; 1379 and 1380; 1381 and 1382; 1383 and 1384; 1385 and 1386; 1387 and 1388; 1389 and 1390; 1391 and 1392; 1393 and 1394; 1395 and 1396; 1397 and 1398; 1399 and 1400; 1401 and 1402; 1403 and 1404; 1405 and 1406; 1407 and 1408; 1409 and 1410; 1411 and 1412; 1413 and 1414; 1415 and 1416; 1417 and 1418; 1419 and 1420; 1421 and 1422; 1423 and 1424; 1425 and 1426; 1427 and 1428; 1429 and 1430; 1431 and 1432; 1433 and 1434; 1435 and 1436; 1437 and 1438; 1439 and 1440; 1441 and 1442; 1443 and 1444; 1445 and 1446; 1447 and 1448; 1449 and 1450; 1451 and 1452; 1453 and 1454; 1455 and 1456; 1457 and 1458; 1459 and 1460; 1461 and 1462; 1463 and 1464; 1465 and 1466; 1467 and 1468; 1469 and 1470; 1471 and 1472; 1473 and 1474; 1475 and 1476; 1477 and 1478; 1479 and 1480; 1481 and 1482; 1483 and 1484; 1485 and 1486; 1487 and 1488; 1489 and 1490; 1491 and 1492; 1493 and 1494; 1495 and 1496; 1497 and 1498; 1499 and 1500; 1501 and 1502; 1503 and 1504; 1505 and 1506; 1507 and 1508; 1509 and 1510; 1511 and 1512; 1513 and 1514; 1515 and 1516; 1517 and 1518; 1519 and 1520; 1521 and 1522; 1523 and 1524; 1525 and 1526; 1527 and 1528; 1529 and 1530; 1531 and 1532; 1533 and 1534; 1535 and 1536; 1537 and 1538; 1539 and 1540; 1541 and 1542; 1543 and 1544; 1545 and 1546; 1547 and 1548; 1549 and 1550; 1551 and 1552; 1553 and 1554; 1555 and 1556; 1557 and 1558; 1559 and 1560; 1561 and 1562; 1563 and 1564; 1565 and 1566; 1567 and 1568; 1569 and 1570; and 1571 and 1572, preferably for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression.

[0114] In accordance with a further aspect, there is provided a double-stranded siRNA, the two strands comprising one of SEQ ID NOs: 1573 and 1574; 1575 and 1576; and 1577 and 1578, preferably for decreasing CCR3 chemokine receptor expression.

[0115] In accordance with a further aspect, there is provided the siRNA described herein, wherein at least one nucleotide of the siRNA is FANA.

[0116] In accordance with a further aspect, there is provided the siRNA described herein wherein at least one adenosine nucleotide of the siRNA is substituted with DAP or an analog thereof.

[0117] In accordance with a further aspect, there is provided the siRNA described herein for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0118] In accordance with a further aspect, there is provided a method for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression in a patient comprising administering a siRNA described herein.

[0119] In accordance with a further aspect, there is provided a method for decreasing CCR3 chemokine receptor expression in a patient comprising administering a siRNA described herein.

[0120] In accordance with a further aspect, there is provided a method for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer in a patient comprising administering a siRNA described herein.

[0121] In accordance with a further aspect, there is provided use of a siRNA described herein for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression or CCR3 chemokine receptor expression or for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0122] In accordance with a further aspect, there is provided a use of a siRNA described herein in the preparation of a medicament for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression; or for decreasing CCR3 chemokine receptor expression; or for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0123] In accordance with a further aspect, there is provided a double-stranded or single-stranded miRNA comprising a pair of oligonucleotides or single oligonucleotide selected from the group consisting of SEQ ID NOs: 1634 and 1635; 1636 and 1637; 1638 and 1639; 1640 and 1641; 1642 and 1643; 1644 and 1645; 1646 and 1647; 1648; 1649 and 1650; 1651 and 1652; 1653 and 1654; 1655 and 1656; 1657 and 1658; 1659; 1660; 1661; 1662; 1663; 1664; 1665; 1666 and 1667; 1668 and 1669; 1670 and 1671; 1672 and 1673; 1674 and 1675; 1676 and 1677; 1678; 1679 and 1680; 1681 and 1682; 1683 and 1684; 1685 and 1686; 1687 and 1688; 1689 and 1690; 1691 and 1692; 1693; 1694; 1695 and 1696; 1697; 1698; 1699 and 1700; 1701; 1702 and 1703; 1704; 1705; 1706; 1707; 1708; 1709; 1710; 1711; 1712 and 1713; 1714 and 1715; 1716; 1717 and 1718; 1719; 1720 and 1721; 1722 and 1723; 1724; 1725 and 1726; 1727; 1728; 1729 and 1730; 1731 and 1732; 1733 and 1734; 1735; 1736; 1737; 1738 and 1739; 1740 and 1741; 1742; 1743 and 1744; 1745; 1746 and 1747; 1748 and 1749; 1750 and 1751; 1752; 1753; 1754; 1755; 1756; 1757; 1758; 1759; 1760; 1761 and 1762; 1763; 1764 and 1765; 1766; 1767 and 1768; 1769; 1770; 1771; 1772; 1773; 1774 and 1775; 1776; 1777; and 1778, preferably for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression.

[0124] In accordance with a further aspect, there is provided the miRNA described herein, wherein at least one nucleotide of the miRNA is FANA.

[0125] In accordance with a further aspect, there is provided the miRNA described herein wherein at least one adenosine nucleotide of the miRNA is substituted with DAP or an analog thereof.

[0126] In accordance with a further aspect, there is provided a method for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression in a patient comprising administering the miRNA described herein.

[0127] In accordance with a further aspect, there is provided a method for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer in a patient comprising administering the miRNA described herein.

[0128] In accordance with a further aspect, there is provided use of the miRNA described herein for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression or for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0129] In accordance with a further aspect, there is provided a use of the miRNA described herein in the preparation of a medicament for decreasing common beta sub-unit of IL-3, IL-5 and GM-CSF receptors expression; or for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer.

[0130] In accordance with a further aspect, there is provided an AON capable of hybridizing under highly stringent conditions with a nucleic acid sequence coding for a protein selected from the group consisting of a CCR3 chemokine receptor and a common beta sub-unit of IL-3, IL-5 and GM-CSF receptors, wherein at least one nucleotide in the oligonucleotide is a 2'-deoxy-2'-fluoroarabinonucleotide (FANA).

[0131] In accordance with a further aspect, there is provided an AON capable of hybridizing under highly stringent conditions with a nucleic acid sequence coding for the protein common beta sub-unit of IL-3, IL-5 and GM-CSF receptors, wherein at least one adenosine nucleotide in the oligonucleotide is substituted with 2-amino-2'-deoxyadenosine (DAP).

[0132] In accordance with a further aspect, there is provided a method for improving the therapeutic efficacy to toxicity ratio of an oligonucleotide administered to a mammal comprising: (a) identifying the oligonucleotide as being intended for administration to the lung and where lowered toxicity is desired; and (b) replacing at least one non-FANA nucleotide with a corresponding FANA nucleotide, and/or substituting at least one adenosine nucleotide with 2-amino-2'-deoxyadenosine (DAP). Preferably, the administration of the resulting oligonucleotide to the mammal results in increased potency of the oligonucleotide and/or decreased toxicity compared to administration of an unmodified oligonucleotide.

[0133] In accordance with a further aspect, there is provided an AON capable of hybridizing under highly stringent conditions with a nucleic acid sequence coding for a protein selected from the group consisting of a CCR3 chemokine receptor and a common beta sub-unit of IL-3, IL-5 and GM-CSF receptors, wherein the internucleotide linkages of the oligonucleotide comprise both phosphodiester and phosphorothioate linkages.

[0134] AONs directed against the common beta subunit of IL-3, IL-5 and GM-CSF, and the CCR3, receptors, and against nucleic acids coding therefor, are, thus, provided. Pharmaceutical compositions comprising the oligonucleotides with a pharmaceutically acceptable carrier are also provided. Uses of the oligonucleotides and methods comprising administering the oligonucleotides for treating and/or preventing at least one of asthma, allergy, CF, hypereosinophilia, general inflammation and cancer are described.

[0135] The terms "nucleic acid" and "nucleic acid molecule" as used interchangeably herein, refer to a molecule comprised of nucleotides, i.e., ribonucleotides, deoxyribonucleotides, or both. The term includes monomers and polymers of ribonucleotides and deoxyribonucleotides, with the ribonucleotide and/or deoxyribonucleotides being connected together, in the case of the polymers, via 5' to 3' linkages. However, linkages may include any of the linkages known in the nucleic acid synthesis art including, for example, nucleic acids comprising 5' to 2' linkages. The nucleotides used in the nucleic acid molecule may be naturally occurring or may be synthetically produced analogues that are capable of forming base-pair relationships with naturally occurring base pairs.

[0136] "Bases" includes any one of the natively found purine and pyrimidine bases, adenine (A), thymine (T), cytosine (C), guanine (G) and uracil (U), but also any modified or analogous forms thereof. Examples of non-naturally occurring bases that are capable of forming base-pairing relationships include, but are not limited to, aza and deaza pyrimidine analogues, aza and deaza purine analogues, and other heterocyclic base analogues, wherein one or more of the ring atoms and/or functional groups of the purine and pyrimidine rings have been substituted by heteroatoms, e.g., carbon, fluorine, nitrogen, oxygen, sulfur, and the like. Preferably, such bases include, but are not limited to, inosine, 5-methylcytosine, 2-thiothymine, 4-thiothymine, 7-deazaadenine, 9-deazaadenine, 3-deazaadenine, 7-deazaguanine, 9-deazaguanine, 6-thioguanine, isoguanine, 2,6-diaminopurine, hypoxanthine, and 6-thiohypoxanthine. Bases may also include, but are not limited to, 5-fluorocytosine, 5-bromocytosine, 5-iodocytosine, isocytosine, N⁴-methylcytosine, 5-iodouracil, 5-fluorouracil, 4-thiouracil, 2-thiouracil, (E)-5-(2-bromovinyl)uracil, N⁶-methyladenine, 2-chloroadenine, 2-fluoroadenine, 2-chloroadenine, N6-cyclopropyl-2,6-diaminopurine, nicotinamide, 2-aminopurine, 1,2,4-triazole-3-carboxamide.

[0137] The term "nucleic acid backbone" as used herein refers to the structure of the chemical moiety linking nucleotides in a molecule. This may include structures formed from any and all means of chemically linking nucleotides. A modified backbone as used herein includes modifications to the chemical linkage between nucleotides, as well as other modifications that may be used to enhance stability and affinity, such as modifications to the sugar structure. For example an α-anomer of deoxyribose may be used, where the base is inverted with respect to the natural β-anomer. In a preferred embodiment, the 2'-OH of the sugar group may be altered to 2'-O-alkyl, R- and S-constrained 2'-O-methyl (R-cMOE and S-cMOE) or 2'-O-alkyl-n(O-alkyl), which provides resistance to degradation without comprising affinity.

[0138] The term "oligonucleotide" as used herein refers to a nucleic acid molecule comprising from about 1 to about 100 nucleotides, more preferably from 1 to 80 nucleotides, and even more preferably from about 4 to about 35 nucleotides. This may include nucleic acid molecules of variable length that correspond either to the sense strand or to the non-coding strand of a target nucleic acid sequence.

[0139] Oligonucleotide compounds in accordance with the present invention also include siRNAs (small interfering RNAs) and the RISCs (RNA-induced silencing complexes) containing them that result from the RNAi (RNA interference) approach. The RNAi approach, which has been described recently, is considered as a new tool for the inhibition of target gene expression. As already known some years ago, RNAi is based on an ancient anti-viral defense mechanism in lower eukaryotes. It is induced by double-stranded RNA and its processing to typically 21-23 nt siRNAs, which cause the degradation of homologous endogenous mRNA after hybridizing to the target mRNA in a single stranded fashion with the assistance of the RISC complex. The way in which RNAi inhibits target gene expression remains to be fully elucidated, but presently, RNAi serves as a first choice approach to generate loss-of-function phenotypes across a broad spectrum of eukaryotic species, such as nematodes, flies, plants, fungi and mammals.

[0140] Oligonucleotide compounds in accordance with the present invention also include microRNA (miRNA). MicroRNA are single-stranded RNA molecules, typically of about 21-23 nucleotides in length, which regulate gene expression in a hybridization dependent manner. Typically, miRNAs are encoded by genes that are transcribed from DNA but not translated into protein (non-coding RNA); instead they are processed from primary transcripts known as pri-miRNA to short stem-loop structures called pre-miRNA and finally to functional miRNA. Mature miRNA molecules are partially complementary to one or more messenger RNA (mRNA) molecules, typically at the 3' end of the mRNA, and their main function is to downregulate gene expression.

[0141] Oligonucleotide compounds in accordance with the present invention also include ribozymes and short nucleotide sequences, single or double stranded, RNA or DNA, which may incorporate chemical modifications as described above, capable of inhibiting gene transcription and/or translation in vitro and/or in vivo.

[0142] The term "modified oligonucleotide" and "modified nucleic acid molecule" includes oligonucleotide compounds that have been modified without significant adverse effect to their activity, for example, by the insertion, substitution or deletion of 1 or more bases. In particular, the addition or deletion of bases at the terminal ends of the oligonucleotides that exhibit 100% complementation to the gene they are directed against can generally be made without significant loss of inhibitory activity. Such modifications may be made in order to increase activity or to provide enhanced stability of the oligonucleotide. In addition, substitution of 1 or more bases in the present oligonucleotide compounds may also be made without adverse effect to activity, for example, substitution of purine with another purine (adenine, guanine) and pyrimidine with pyrimidine (cytosine, thymine, uracil). Modified oligonucleotide and modified nucleic acid molecule as used herein also include nucleic acids, including oligonucleotides, with one or more chemical modifications at the molecular level of the natural molecular structures of all or any of the nucleic acid bases, sugar moieties, internucleoside phosphate linkages, as well as molecules having added substituents, such as diamines, cholesteryl or other lipophilic groups, or a combination of modifications at these sites. Modified nucleotides may include a nucleotide substitute selected from the group consisting of 2-amino-2'-deoxyadenosine and analogs. Preferred adenosine analogs include 2,6-diaminoadenosine hemisulfate, 2-amino-9-(B-D-2'-deoxyribofuranosyl)adenosine, 7-deaza-2'-deoxyadenosine, N6-methyl-2'-deoxyribofuranosyl adenosine, 2-aminoadenosine/2,6-diaminopurine riboside, salts and functional derivatives thereof. The internucleoside phosphate linkages can be phosphodiester, phosphotriester, phosphoramidate, siloxane, carbonate, carboxymethylester, acetamidate, carbamate, thioether, bridged phosphoranidate, bridged methylene phosphonate, phosphorothioate, methylphosphonate, phosphorodithioate, bridged phosphorothioate and/or sulfone internucleotide linkages, or 3'-3',2'-5' or 5'-5'linkages, and combinations of such similar linkages (to produce mixed backbone modified oligonucleotides). The modifications can be internal (single or repeated) or at the end(s) of the oligonucleotide molecule and can include additions to the molecule of the internucleoside phosphate linkages, such as cholesteryl, diamine compounds with varying numbers of carbon residues between amino groups and terminal ribose, deoxyribose and phosphate modifications which cleave or cross-link to the opposite chains or to associated enzymes or other proteins. Electrophilic groups such as ribose-dialdehyde may be covalently linked with an epsilon amino group of the lysyl-residue of such a protein. A nucleophilic group such as n-ethylmaleimide tethered to an oligomer could covalently attach to the 5' end of an mRNA or to another electrophilic site. The term modified oligonucleotides also includes oligonucleotides comprising modifications to the sugar moieties such as 2'-substituted ribonucleotides, or deoxyribonucleotide monomers, any of which are connected together via 5' to 3' linkages. Modified oligonucleotides may also be comprised of PNA or morpholino modified backbones where target specificity of the sequence is maintained. The term modified oligonucleotides also includes oligonucleotide compounds, as defined herein, of a form that does not significantly adversely affect their activity to reduce activity or inhibit expression of a target protein, but which may enhance this activity.

[0143] Modified oligonucleotides also include oligonucleotides that are based on or constructed from arabinonucleotide or modified arabinonucleotide residues, including but not limited to AON constructs based on beta-arabinofuranose and its analogues. Aribonucleosides are stereoisomers of ribonucleosides, differing only in the configuration at the 2'-position of the sugar ring. International Patent Application Publication No. WO 99/67378 discloses arabinonucleic acid (ANA) oligomers and their analogues for improved sequence specific inhibition of gene expression via association to complementary messenger RNA. International Patent Application Publication No. WO 99/67378 further teaches sugar-modified oligonucleotides that form a duplex with its target RNA sequence resulting in a substrate for RNaseH. Specifically, oligomers comprising beta-D-arabinonucleotides and 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides (FANA or 2'F-ANA) are disclosed. International Patent Application Publication No. WO 02/20773 discloses oligonucleotide chimeras used to inhibit gene transcription and expression in a sequence specific manner. Specifically, International Patent Application Publication No. WO 02/20773 teaches AONs constructed from arabinonucleotides flanking a series of deoxyribose nucleotide residues of variable length. AONs so constructed are used to hybridize and induce cleavage of complementary RNA. International Patent Application Publication No. WO 03/037909 discloses oligonucleotides having an internal acyclic linker residue. AONs prepared with an acyclic linker are used to prevent or deplete function of a target nucleic acid of interest such RNA. International Patent Application Publication No. WO 03/064441 discloses oligonucleotides having alternating segments of sugar-modified nucleosides and 2' deoxynucleosides and also alternating segments of sugar-modified nucleotides and 2' deoxynucleotides. AONs having these alternating segments are disclosed to be used to prevent or deplete function of a target nucleic acid of interest such as RNA.

[0144] Moreover, the skilled artisan recognizes that substantially similar nucleic acid sequences encompassed by this invention are also defined by their ability to hybridize, under moderately stringent conditions (for example, 0.5×SSC, 0.1% SDS, 60° C.) with the sequences exemplified herein, or to any portion of the nucleotide sequences disclosed herein and which are functionally equivalent to any of the nucleic acid sequences disclosed herein. Stringency conditions can be adjusted to screen for moderately similar fragments, such as homologous sequences from distantly related organisms, to highly similar fragments, such as genes that duplicate functional enzymes from closely related organisms. Post-hybridization washes determine stringency conditions. One set of preferred conditions involves a series of washes starting with 6×SSC, 0.5% SDS at room temperature for 15 min, then repeated with 2×SSC, 0.5% SDS at 45° C. for 30 min, and then repeated twice with 0.2×SSC, 0.5% SDS at 50° C. for 30 min. A more preferred set of highly stringent conditions involves the use of higher temperatures in which the washes are identical to those above except the temperature of the final two 30 min. washes in 0.2×SSC, 0.5% SDS was increased to 60° C. Another preferred set of very highly stringent conditions involves the use of two final washes in 0.1×SSC, 0.1% SDS at 65° C.

[0145] The term "substantially nuclease resistant" refers to nucleic acids that are resistant to nuclease degradation, as compared to naturally occurring or unmodified nucleic acids. Modified nucleic acids of the invention are at least 1.25 times more resistant to nuclease degradation than their unmodified counterpart, more preferably at least 2 times more resistant, even more preferably at least 5 times more resistant, and most preferably at least 10 times more resistant than their unmodified counterpart. Such substantially nuclease resistant nucleic acids include, but are not limited to, nucleic acids with modified backbones such as phosphorothioates, methylphosphonates, ethylphosphotriesters, 2'-O-methylphosphorothioates, 2'-O-methyl-p-ethoxy ribonucleotides, 2'-O-alkyls, 2'-O-alkyl-n(O-alkyl), 3'-O-alkyls, 3'-O-alkyl-n(O-alkyl), 2'-fluoros, 2'-deoxy-erythropentofuranosyls, 2'-O-methyl ribonucleosides, R- and S-constrained 2'-O-methyl ribonucleosides (R-cMOE and S-cMOE), methyl carbamates, and methyl carbonates; nucleic acids with modified bases such as inverted bases (e.g., inverted T's); or chimeric versions of any of the above.

[0146] The term "CCR3 and common beta-chain for IL-3/IL-5/GM-CSF receptors AON" as used herein refers to an oligonucleotide that is targeted to sequences specific for the CCR3 chemokine receptor and the common beta-chain for IL-3/IL-5/GM-CSF receptors, and inhibits CCR3 and common beta-chain for IL-3/IL-5/GM-CSF receptors expression and/or activity. These include, but are not limited to, CCR3 chemokine receptor and the common beta-chain for IL-3/IL-5/GM-CSF receptors, DNA coding sequences, DNA promoter sequences, DNA enhancer sequences, intron-exon junctions, 5' and 3' UTR, mRNA coding sequences, and the like.

[0147] As discussed above, one embodiment of the present invention provides AON targeted to sequences that affect CCR3 chemokine receptor and the common β-chain for IL-3/IL-5/GM-CSF receptors expression and/or activity. In one embodiment, the AON may comprise fragments or variants of these sequences, as will be understood by a person skilled in the art, that may alter the oligonucleotide make-up and/or length, but which maintains or increases the activity of the oligonucleotide to down-regulate gene expression. In another embodiment the present invention provides for combinations of at least two AON from the sequences described herein.

[0148] The terms "treatment", "treating", "therapy" and the like are used herein to generally mean obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or amelioration of an adverse effect attributable to the disease. "Treatment" as used herein covers any treatment of a disease in a subject as previously defined, particularly a human, and includes:

[0149] (a) preventing a disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it;

[0150] (b) inhibiting a disease, i.e., arresting its development; or

[0151] (c) relieving a disease, i.e., causing regression of the disease.

[0152] The term "pharmaceutically acceptable" as it is used herein with respect to carriers, surfactants and compositions refers to substances which are acceptable for use in the treatment of a subject patient that are not toxic or otherwise unacceptable for administration by any of the routes herein described.

[0153] The invention is generally directed toward the treatment of subjects by the administration of therapeutically effective amounts of AON compounds in accordance with the present invention, including siRNA; miRNA and miRNA mimics; ribozymes; short nucleotide sequences, single or double stranded, including RNA and/or DNA that may be complementary to a target nucleic acid, or may optionally be modified as described above; an RNA oligonucleotide having at least a portion of said RNA oligonucleotide capable of hybridizing with RNA to form an oligonucleotide-RNA duplex; or a chimeric oligonucleotide, that will downregulate or inhibit the expression of an endogenous gene in vivo.

[0154] By "therapeutically effective" amount is meant a nontoxic but sufficient amount of an antisense oligonucleotide compound to provide the desired therapeutic effect. In the present case, that dose of AON compound effective to relieve, ameliorate, or prevent symptoms of the condition or disease being treated, e.g. disease associated with allergy, asthma, inflammatory disease such as inflammatory respiratory disease.

[0155] The term "allergy" as used herein, describes any undesirable immune response by the body to a substance to which it has become hypersensitive.

[0156] The formulations of the present invention are preferably administered directly to the site of action and, thus, preferably are topical, including but not limited to, oral, intrabuccal, intrapulmonary, rectal, intrauterine, intratumor, nasal, intrathecal, inhalable, transdermal, intradermal, intracavitary, iontophoretic, ocular, vaginal, intraarticular, otical, transmucosal, rectal, slow release or enteric coating formulations. Without limiting any of the foregoing, formulations of the present invention may also be intracranial, intramuscular, subcutaneous, intravascular, intraglandular, intraorgan, intralymphatic, intraperitoneal, intravenous, and implantable. The carriers used in the formulations may be, for example, solid and/or liquid carriers.

[0157] Reference may be made to "Remington's Pharmaceutical Sciences", 17th Ed., Mack Publishing Company, Easton, Pa., 1985, for other carriers that would be suitable for combination with the present oligonucleotide compounds to render compositions/formulations suitable for administration to treat respiratory disease.

[0158] Optionally, the presently described oligonucleotides may be formulated with a variety of physiological carrier molecules. The presently described oligonucleotides may also be complexed with molecules that enhance their ability to enter the target cells. Examples of such molecules include, but are not limited to, carbohydrates, polyamines, amino acids, peptides, lipids, and molecules vital to cell growth. For example, the oligonucleotides may be combined with a lipid, the resulting oligonucleotide/lipid emulsion, or liposomal suspension may, inter alia, effectively increase the in vivo half-life of the oligonucleotide.

[0159] The pharmaceutical compositions provided herein may comprise oligonucleotide compounds described above and one or more pharmaceutically acceptable surfactants. Suitable surfactants or surfactant components for enhancing the uptake of the oligonucleotides of the invention have been previously described in U.S. Application Publication No. 2003/0087845, the contents of which are incorporated herein with respect to surfactants. The application states that suitable surfactants " . . . include synthetic and natural as well as full and truncated forms of surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant protein E, di-saturated phosphatidylcholine (other than dipalmitoyl), dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine; phosphatidic acid, ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol, glycero-3-phosphocholine, dihydroxyacetone, palmitate, cytidine diphosphate (CDP) diacylglycerol, CDP choline, choline, choline phosphate; as well as natural and artificial lamelar bodies which are the natural carrier vehicles for the components of surfactant, omega-fatty acids, polyenic acid, polyenoic acid, lecithin, palmitinic acid, non-ionic block copolymers of ethylene or propylene oxides, polyoxypropylene, monomeric and polymeric, polyoxyethylene, monomeric and polymeric, poly (vinyl amine) with dextran and/or alkanoyl side chains, Brij 35®, Triton X-100® and synthetic surfactants ALEC®, Exosurf®, Survan® and Atovaquone®, among others. These surfactants may be used either as single or part of a multiple component surfactant in a formulation, or as covalently bound additions to the 5' and/or 3' ends of the AONs."

[0160] The oligonucleotide component of the present compositions may be contained in a pharmaceutical formulation within a lipid particle or vesicle, such as a liposome or microcrystal. As described in U.S. Pat. No. 6,025,339, the lipid particles may be of any suitable structure, such as unilamellar or plurilamellar, so long as the oligonucleotide is contained therein. Positively charged lipids such as N-[1-(2,3-dioleoyloxi) propyl]-N,N,N-trimethyl-ammoniumethylsulfate, or "DOTAP," are particularly preferred for such particles and vesicles. The preparation of such lipid particles is well known. See, e.g., U.S. Pat. Nos. 4,880,635 to Janoff et al.; 4,906,477 to Kurono et al.; 4,911,928 to Wallach; 4,917,951 to Wallach; 4,920,016 to Allen et al.; 4,921,757 to Wheatley et al.; etc.

[0161] The composition of the invention may be administered by any means that transports the oligonucleotide compound to the desired site, such as for example, the lung. The oligonucleotide compounds disclosed herein may be administered to the lungs of a patient by any suitable means, but are preferably administered by inhalation of an aerosol comprised of respirable particles that comprise the oligonucleotide compound.

[0162] The oligonucleotides may be formulated to be administered in a dry powder inhaler, metered dose inhaler, nebulizer, soft mist inhaler and by any other suitable device having the capacity to deliver oligonucleotides to the lungs via inhalation route.

[0163] The composition of the present invention may be administered into the respiratory system as a formulation including particles of respirable size, e.g. particles of a size sufficiently small to pass through the nose, mouth and larynx upon inhalation and through the bronchi and alveoli of the lungs. In general, respirable particles range from about 0.5 to 10 microns in size. Particles of non-respirable size that are included in the aerosol tend to deposit in the throat and be swallowed, and the quantity of non-respirable particles in the aerosol is preferably thus minimized. For nasal administration, a particle size in the range of 10-500 μM is preferred to ensure retention in the nasal cavity.

[0164] A solid particulate composition comprising the oligonucleotide compound may optionally contain a dispersant that serves to facilitate the formation of an aerosol as well as other therapeutic compounds. A suitable dispersant is lactose, which may be blended with the antisense compound in any suitable ratio, e.g., a 1 to 1 ratio by weight.

[0165] Liquid pharmaceutical compositions of active compound (the oligonucleotide compound(s)) for producing an aerosol may be prepared by combining the oligonucleotide compound with a suitable vehicle, such as sterile pyrogen free water or phosphate buffered saline.

[0166] The oligonucleotide compositions may be administered in an anti-bronchoconstriction, anti-allergy(ies) and/or anti-inflammatory effective amount, which amount depends upon the degree of disease being treated, the condition of the subject patient, the particular formulation, the route of administration, the timing of administration to a subject, etc. In general, intracellular concentrations of the oligonucleotide of from 0.05 to 50 μM, or more particularly 0.2 to 5 μM, are desirable. For administration to a mammalian patient such as a human, a dosage of about 0.001, 0.01, 0.1, or 1 mg/Kg up to about 50, or 100 mg/Kg or more is typically employed. However, other doses are also contemplated. Depending on the solubility of the active compound in any particular formulation, the daily dose may be divided among one or several unit dose administrations.

[0167] The aerosols of liquid particles comprising the oligonucleotide compound may be produced by any suitable means, such as with a nebulizer. Nebulizers are commercially available devices that transform solutions or suspensions of the active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air or oxygen, through a narrow venturi orifice or by means of ultrasonic agitation. Suitable formulations for use in nebulizers comprise the active oligonucleotide ingredient in a liquid carrier in an amount of up to 40% w/w preferably less than 20% w/w of the formulation. The carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not prepared sterile, for example, methyl hydroxybenzoate, anti-oxidants, anti-bacterials, flavorings, volatile oils, buffering agents and emulsifiers and other formulation surfactants.

[0168] The aerosols of solid particles comprising the active oligonucleotide compound(s) and a pharmaceutically acceptable surfactant may likewise be produced with any solid particulate medicament aerosol generator. Aerosol generators for administering solid particulate medicaments to a subject produce particles that are respirable, as explained above, and generate a volume of aerosol containing a predetermined metered dose of a medicament at a rate suitable for human administration. The active oligonucleotide ingredient typically comprises from 0.1 to 100 w/w of the formulation. A second type of illustrative aerosol generator comprises a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquified propellant. During use these devices discharge the formulation through a valve adapted to deliver a metered volume, typically from 10 to 150 μL, to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or hydrofluoroalkanes and mixtures thereof. The formulation may additionally contain one or more co-solvents, for example, ethanol, emulsifiers and other formulation surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavoring agents.

[0169] The aerosol, whether formed from solid or liquid particles, may be produced by the aerosol generator at a rate of from about 1 to 150 liters per minute.

[0170] In a further aspect of the present invention, an article of manufacture is provided which includes packaging material contained within which is a pharmaceutically acceptable oligonucleotide composition that is therapeutically effective to treat conditions associated with allergy, asthma, rhinitis and inflammatory disease. In one embodiment, the composition comprises an oligonucleotide compound that is effective to inhibit CCR3 chemokine receptor or the common beta-chain for IL-3/IL-5/GM-CSF receptors gene expression, said oligonucleotide compound being at least 50% complementary to the gene. In another aspect, the composition comprises at least 2 oligonucleotide compounds, each oligonucleotide compound being capable of downregulating expression of each of the CCR3 chemokine receptor and the common beta-chain for IL-3/IL-5/GM-CSF receptors genes, each oligonucleotide compound being present at a concentration at which the oligonucleotide compound is practically ineffective on its own to downregulate the gene it is directed against, the combination of the oligonucleotide compounds being effective to downregulate at least one of the genes that the oligonucleotides are directed against.

[0171] In one embodiment, the packaging material of the article comprises a label which indicates that the composition can be used to treat inflammatory respiratory disease and may additionally include an indication that the disease is one of allergy, rhinitis, COPD, CF, and asthma.

[0172] In another embodiment, the packaging material of the article comprises a label which indicates that the composition can be used to treat inflammatory respiratory disease, and may additionally include an indication that the disease is one of allergy, asthma, hypereosinophilia, bronchitis, COPD, rhinitis or sinusitis.

[0173] For the purposes of the present invention, the packaging material may be any suitable material for packaging a nucleotide-containing composition in accordance with the present invention, including a bottle or other container (either plastic or glass), a carton, a tube, or other protective wrapping. As will be appreciated, the packaging may vary with the nature of the oligonucleotide composition, for example, a liquid formulation may be packaged differently than an aerosol formulation.

[0174] The present invention will be more readily understood by referring to the examples that are given to illustrate the following invention rather than to limit its scope. With respect to these examples, the following were methods and materials were used.

EXAMPLES

Methods

Cell Culture

[0175] TF-1 cells were cultured in RPMI-1640 medium containing 2 mM L-glutamine, 1.5 g/l sodium bicarbonate, 4.5 g/l D-glucose, 10 mM HEPES, 1 mM sodium pyruvate, 10% fetal bovine serum, 2 ng/ml rhGM-CSF, 100 U/ml penicillin and 100 μg/ml streptomycin. 293-βc-GFP and 293-CCR3-GFP cells stably expressing β-chain-GFP and CCR3-GFP fusion cDNA, respectively, were cultured in DMEM containing 2 mM L-glutamine, 4.5 g/l glucose, 10% fetal bovine serum, 15 μg/ml Blasticidin, 100 μg/ml Hygromycin B, 100 U/ml penicillin and 100 μg/ml Streptomycin. NIH-3T3 cells were cultured in DMEM containing 2 mM L-glutamine, 4.5 g/l glucose, 10% calf bovine serum, 100 U/ml penicillin and 100 μg/ml Streptomycin.

Design and Preparation of AON, siRNA and miRNA Mimic Sequences

[0176] Phosphorothioate-DNA AONs (Sigma Genosys), DAP-modified phosphorothioate-DNA AONs (Sigma Genosys) and phosphorothioate-2'F-ANA AONs (Topigen, Montreal or UCDNA, Calgary) were designed to target the coding regions of the β-chain and CCR3 mRNAs. Phosphorothioate-DNA AONs, specifically, were designed to target regions along the entire coding region of the β-chain mRNA, as well as within the 5' UTR, 3' UTR and regions extending across intron/exon junctions. Online reference sequences (NCBI Genbank entries) used for the design of β-chain and CCR3 AON were: Genbank accession numbers BC070085 (TOP050 (SEQ ID No: 1)-TOP076 (SEQ ID No: 27), TOP195 (SEQ ID No: 146), and TOP254 (SEQ ID No: 205)-TOP259 (SEQ ID No: 210)); NM_--000395.2 (TOP077 (SEQ ID No: 28)-TOP194 (SEQ ID No: 145), TOP196 (SEQ ID No: 147)-253 (SEQ ID No: 204), TOP260 (SEQ ID No: 211)-TOP346 (SEQ ID No: 297) and TOP517 (SEQ ID No: 468)-TOP721 (SEQ ID No: 672)); and NG_--008040 (TOP347 (SEQ ID No: 298)-TOP516 (SEQ ID No: 467)) for β-chain; and NM_--001837 (TOP020 (SEQ ID NO. 673)-TOP045 (SEQ ID NO. 698)) for CCR3. SiRNA sequences were designed using conventional Tuschl-based design (Qiagen siRNA design tool), High Performance (HP) OnGuard algorithm (Genome Wide siRNA, Qiagen), Thermoscientific Dharmacon RNAi Technologies siDESIGN Center Custom siRNA Design Tool (www.thermo.com/sidesign), Invitrogen's BLOCK-IT® RNAi Designer (https://rnaidesigner.invitrogen.com), or EMBOSS (https://anabench.bcm.umontreal.ca/html/EMBOSS/runs/file6LGF4f/ind- ex.html).

[0177] MiRNA mimics were selected using publicly available algorithms to identify miRNAs with homology to the 3' UTR of the β-chain gene. Algorithms employed for identification of miRNAs were TargetScan (http://www.targetscan.org/), miRBase (http://microrna.sanger.ac.uk/cgi-bin/targets/v5/search.pl), miRANDA (http://www.microrna.org/microrna/getGeneForm.do), miRGEN (http://www.diana.pcbi.upenn.edu/cgi-bin/miRGen/v3/Targets.cgi) and DIANA microT (http://diana.cslab.ece.ntua.gr/microT/).

[0178] All oligonucleotides were resuspended in sterile water and their concentrations determined by spectrophotometry.

Cell Transfection

[0179] TF-1 cells in exponential growth phase (0.6 to 0.8×10⁶ cells/ml) were grown at a density of 1.25×10⁶ cells/ml in complete growth medium without antibiotics. Cells were immediately transfected with AON-, siRNA- or miRNA mimic-Lipofectamine 2000 complexes diluted in Opti-MEM and previously incubated for 20 minutes at room temperature at a ratio of 1 μg oligonucleotide:1 μl Lipofectamine 2000. Cells were transfected with AON concentrations ranging between 83.5 nM and 2.67 μM, siRNA concentrations ranging between 0.25 and 1.0 μM, and miRNA mimics at concentrations of 0.5 μM and 1 μM, then incubated at 37° C. for 18 to 72 hours.

[0180] 293-βc-GFP and 293-CCR3-GFP cells were cultured in complete growth medium without antibiotics. Cells were transfected as described above with AON concentrations between 67 nM and 534 nM or siRNA concentrations between 40 nM and 1.0 μM. CCR3-GFP or β-chain-GFP expression was induced with 100 ng/ml doxycycline for 2 hours (mRNA) or 18 hours (protein) prior to harvesting.

[0181] NIH 3T3 cells were transfected as described above with 0.2 μg pCMVscript rat CCR3 or 0.3 μg pGL2-Luciferase, and 0.2 μg of AON.

Quantification of mRNA Expression

[0182] Quantification of the mRNA expression levels of CCR3 and β-chain was performed using the Quantigene 2.0 assay. Briefly, cells were resuspended in 1× Quantigene lysis mixture and incubated at 53-55° C. for 30 minutes. The only exception was for CCR3 mRNA quantification in TF-1 cells for which total RNA was first extracted from cell pellets using the RNAeasy mini kit and quantified using the Ribogreen assay according to the manufacturer protocols. Cell lysates or purified RNA were then hybridized overnight at 55° C. using specific probe sets and signal detection performed according to the Quantigene 2.0 assay procedure. Gene expression was normalized relative to the expression of a control gene (β2M).

Quantification of βc-GFP and CCR3-GFP Protein Expression in 293 Cells by Flow Cytometry

[0183] Cells were harvested with trypsin 24 hours post-transfection, washed twice with PBS, resuspended in 1× permeabilization solution and incubated for 10 minutes at room temperature. Cells were then washed twice with PBS containing 0.5% BSA, resuspended in 50 μL PBS containing 5 μg/ml FITC-conjugated anti-GFP antibody and incubated for 1 hour at 4° C. Cells were washed twice with PBS and fixed in 2% paraformaldehyde before analysis by flow cytometry (488 nM) using the GUAVA EasyCyte apparatus.

Quantification of Endogenous Protein Expression in TF-1 by FACS

[0184] TF-1 cells were harvested at indicated time points post-transfection and washed twice with PBS. The staining was performed on 50,000 cells using the Eotaxin Fluorokine kit for CCR3 receptor quantification or the IL-3 Fluorokine kit for common β-chain of IL-3, IL-5 and GM-CSF receptors. In these assays, biotinylated eotaxin or biotinylated IL-3 binds to the specific cell surface receptor and is detected using avidin-fluorescein. Cells were fixed in 4% paraformaldehyde solution and green fluorescence was detected by FACS (488 nM) using the GUAVA EasyCyte apparatus.

AON Serum Stability Assay

[0185] AON were dried down and resuspended in DMEM supplemented with 50% fetal bovine serum at a final concentration of 1 μg/μl. AONs were incubated at 37° C. and samples (20 μl) collected at different time points between 0 and 96 hours and stored at -80° C. until analysis. Samples were dried down, resuspended in 100 μl dH₂O and loaded on ProteinPak® DEAE-5PW anion exchange column (7.5×75 mm) for HPLC analysis.

Antisense Efficacy in a Rat Model of Allergen-Induced Airway Inflammation

[0186] Animal studies were conducted at Mispro Biotech Services, Montreal, QC and were approved by Mispro's Animal Ethic Committees. Brown Norway (BN) rats (6 to 8 weeks old) were obtained from Harlan Sprague-Dawley Inc. Active sensitization was performed by subcutaneous injection of 1 ml of saline containing 1 mg of chicken egg ovalbumin (OVA) and 3.5 mg of aluminum hydroxide gel. Fourteen days after sensitization, rats were injected intra-tracheally (i.t.) with either sterile saline (50 μl) or 50 μg of a combination of TOP006 (SEQ ID No: 1626) and TOP007 (SEQ ID No: 1628) (ratio w/w 1:1) or 50 μg of a combination TOP006-F2 (SEQ ID No: 1627) and TOP007-F8 (SEQ ID No: 1629) (ratio w/w 1:1) in 50 μl sterile saline. Rats were challenged 10 minutes later by exposure to OVA aerosols (5% in saline) in a closed chamber for 15 minutes. Challenge was repeated 24 hours later. To determine the effect of AON treatment on cellular influx to the lungs, rats were sacrificed 15 hours following second OVA challenge, and bronchoalveolar lavages (BAL) were performed. Cells were recovered by centrifugation and total leukocyte counts were performed using a hemacytometer. Differential cell counts were performed on cytospin slides stained with Hema-3 stain kit. At least 200 cells were counted under oil immersion microscopy. Lungs were collected following BAL and processed for mRNA (right lung) or immunohistochemistry (left lung).

Animal Inhalation Studies

Monkey Study Design

[0187] All studies were performed at ITR Laboratories Canada (Baie d'Urfe, QC) in compliance with GLP regulations. Briefly, male and female cynomolgus monkeys (weighing 1.5-2.5 kg) received 14 consecutive doses of vehicle or 0.05, 0.25 or 2.5 mg/kg of TPI ASM8 (in saline) or TPI 1100 (in phosphate-buffered saline; PBS) administered daily as aerosols using a inhalation exposure system. The animals were examined 1-2 times daily for clinical symptoms including a qualitative assessment of food consumption, and body weight was measured weekly. Electrocardiographic (ECG) activity was recorded and ophthalmic examinations were conducted for animals pre-study and on Day 14.

[0188] One day after the last dose (Day 15), 24 monkeys (3/sex/group) were euthanized. All remaining animals were euthanized upon completion of the recovery period (14 day after the last dose for the TPI ASM8 study or 28 days after the last dose for the TPI 1100 study). Terminal procedures included complete gross necropsy examination, collection and preservation of approximately 40 tissues, and measurement of the weights of all major organs. Respiratory tract tissues (nasal cavity, nasopharynx, larynx, pharynx, trachea, bronchi, lungs including carina and bronchial lymph nodes) from all animals were examined by light microscopy, and all collected tissues was examined for all high dose and control group animals. In addition, portions of the trachea, lung, liver and kidney were collected for analysis of AON content.

Rodent Study Design

[0189] Studies in rat (TPI ASM8) and in mice (TPI 1100) were conducted as described for the monkey studies. Male and female CD-1 mice received 14 consecutive doses of vehicle or 0.05, 0.25 or 2.5 mg/kg of TPI 1100 administered daily as aerosols using an inhalation exposure system. Male and female Sprague-Dawley rats received 14 consecutive doses of vehicle or 0.02, 0.07, 0.2 0.1 or 5 mg/kg of TPI ASM8 administered daily as aerosols using an inhalation exposure system.

Example 1

Efficacy of AON Sequences Directed to the Common Beta Subunit of IL-3, IL-5 and GM-CSF Receptors

[0190] The sequence and composition of the AON sequences directed against the common beta subunit (β-chain) of IL-3, IL-5 and GM-CSF receptors are presented in Table 1a. All AONs were purified and desalted. The potency of some selected sequences is demonstrated in FIG. 1a which shows the reduction in gene expression in vitro following transfection with indicated AON in 293-βc-GFP and TF-1 cell lines. AON activity listed in Table 1a, is expressed as the average percentage inhibition of β-chain mRNA relative to untransfected controls. The 293-βc-GFP cell line was engineered to artificially express β-chain/green fluorescent protein (GFP) fusion mRNA and protein while TF-1 cells express β-chain mRNA and protein endogenously.

[0191] Specificity of some selected AON sequences was assessed by comparing their efficacy at reducing β-chain mRNA expression levels compared to their respective control sense sequence in 293-βc-GFP cells (FIG. 1b) and in TF-1 cells (FIG. 1c). In each cell line, respective control sense sequences which are not complementary to the β-chain mRNA were inactive. In addition, inhibitory activity of AON targeting β-chain was also observed at the protein level upon analysis by flow cytometry. FIGS. 5a and 5b show that 293-βc-GFP and TF-1 cells had decreased levels of β-chain protein expression following transfection with specific AON and overnight incubation while control sequences had no effect.

Example 2

Efficacy of AON Sequences Directed to the CCR3 Chemokine Receptor

[0192] The list of AON sequences targeting CCR3 is presented in Table 1b. All AON were prepared and purified as described above. The potency of some selected sequences is demonstrated in FIG. 2a which shows the reduction in gene expression in vitro following transfection with indicated AON in 293-CCR3-GFP and TF-1 cell lines. The 293-CCR3-GFP cell line was engineered to express a CCR3/green fluorescent protein (GFP) fusion product while TF-1 cells express CCR3 mRNA and protein endogenously. FIGS. 2b and 2c show the specific reduction in CCR3 mRNA expression levels in 293-CCR3-GFP and TF-1 cells, respectively, 24 hours post-transfection with AONs against CCR3, whereas respective control sense sequences were inactive. AON activity given in Table 1b is expressed as the average percentage inhibition of CCR3 mRNA expression relative to untransfected controls.

[0193] The inhibitory activity of AON targeting CCR3 was also observed at the protein level upon analysis by flow cytometry. FIGS. 5c and 5d show that 293-CCR3-GFP and TF-1 cells had decreased levels of CCR3 protein expression 24 hours post-transfection with indicated AON, while control sequences had no effect.

Example 3

Comparison Between AON and siRNA Sequences at Reducing β-Chain mRNA Expression

[0194] In addition to AON sequences, siRNA molecules were designed (Table 2a) and tested for their efficacy at reducing β-chain mRNA expression (FIG. 3). FIG. 3a shows the efficacy of some selected siRNA sequences at reducing β-chain mRNA expression levels in 293-βc-GFP cells compared to untransfected cells (Ctl NT) and to an irrelevant siRNA sequence (siCtl). The efficacy of AON TOP062 (SEQ ID No: 13) at reducing β-chain mRNA expression in TF-1 cells was compared to different siRNA sequences designed to target common β-chain. Results indicated that AON TOP062 (SEQ ID No: 13) (0.5 and 1 μM) exhibited superior efficacy at reducing β-chain mRNA expression compared to the siRNA sequences (FIG. 3b). In addition, time-course experiments indicated that inhibition of β-chain mRNA expression in cells transfected with AON TOP062 (SEQ ID No: 13) was maintained up to 72 h post-transfection while all the siRNA sequences evaluated were ineffective at reducing expression at this time point (FIG. 3c).

Example 4

Comparison Between AON and siRNA Sequences at Reducing CCR3 mRNA Expression

[0195] In addition to AON sequences, siRNA molecules were designed (Table 2b) and tested for their efficacy at reducing CCR3 mRNA expression (FIG. 4). FIG. 4a shows the efficacy of some selected siRNA sequences at reducing CCR3 mRNA expression levels in 293-CCR3-GFP cells compared to untransfected cells (Ctl NT) and to an irrelevant siRNA sequence (siCtl). The efficacy of AON TOP030 (SEQ ID No: 683) at reducing CCR3 mRNA expression in 293-CCR3-GFP cells was compared to different siRNA sequences designed to target CCR3 (FIG. 4b). Time-course experiments indicated that inhibition of CCR3 mRNA expression in cells transfected with AON TOP030 (SEQ ID No: 683) was maintained up to 72 hours post-transfection while only one siRNA sequence (siCCR3_--1HP) maintained inhibitory activity at this time point.

Example 5

AONs Modified with FANA Chemistry Demonstrated Increased Efficacy and Prolonged Serum Stability

[0196] This example relates to the enhanced efficacy and prolonged serum stability of β-chain and CCR3-specific AONs when ANA modifications are incorporated into the chemistry of the AON. Tables 3a and 3b describe the compositions of AON modified with FANA residues. In FIG. 6a, results obtained for O-chain expression in 293-βc-GFP cells transfected with β-chain-specific AONs (unmodified DNA with phosphorothioate backbone or FANA modified as indicated) are provided. Modification of TOP062 (SEQ ID No: 13) sequence with FANA (TOP062-F2 (SEQ ID No: 1582) and TOP062-F3 (SEQ ID No: 1583)) enhanced the efficacy of the AON as shown by the increased inhibition of target protein expression, clearly indicating an advantage of this modification for AON activity. Similarly, modification of TOP030 (SEQ ID No: 683) sequence with FANA (TOP030-F12) (SEQ ID No: 1610) enhanced its efficacy to inhibit CCR3 protein expression, again supporting the advantage of this modification for AON activity (FIG. 6b). The FANA modifications also enabled the incorporation of natural phosphodiester linkages without affecting the activity of the AON on expression of the respective mRNA target (TOP062-F14 (SEQ ID No: 1594) to F18 and TOP030-F12 (SEQ ID No: 1610)) (Table 3a and 3b). This was surprising as phosphodiester-containing AONs are commonly believed to be more susceptible to nuclease degradation, resulting in reduced antisense inhibitory activity compared to phosphorothioate-containing AON counterparts.

[0197] FANA modifications are expected to enhance the stability of the AON, rendering it more resistant to nucleosidase digestion, further resulting in prolonged AON activity. FIG. 5 presents the comparison of different formulations of TOP062 (SEQ ID No: 13) (β-chain) and TOP030 (SEQ ID No: 683) (CCR3) diluted DMEM containing 50% fetal bovine serum and incubated at 37° C. for indicated time period. Aliquots were collected at different time points and the presence of intact AON analyzed using HPLC. Results showed that incorporation of FANA modified nucleotides in TOP062 (SEQ ID No: 13) (FIG. 7a) and TOP030 (SEQ ID No: 683) (FIG. 7b) conferred significant resistance to serum-mediated degradation.

Example 6

Cross-Target Effect of an AON Specific for One Receptor on the Expression of Another Receptor

[0198] This example relates to the effect of inhibition of a single receptor on mRNA production of a different receptor. The experiments were conducted in TF-1 cells. Although AON sequences were specifically designed against their respective target, results in FIG. 8 and FIG. 9 show that several AON were found not only to inhibit their specific targets but were able to down regulate mRNA corresponding to other receptors (cross-target effect). CCR3 specific AON TOP030-F2 (SEQ ID No: 1600) not only provided inhibition of its specific target (FIGS. 8a and 8b) but also downregulated mRNA (FIG. 8c) and protein (FIG. 8d) expression of common β-chain.

[0199] Similarly, AONs TOP031 (SEQ ID No: 684) and TOP037 (SEQ ID No: 690) downregulated expression of CCR3 (FIG. 9a) and additionally demonstrated inhibitory activity towards common β-chain protein expression (FIG. 9b).

[0200] Conversely, besides downregulating expression of its specific target, common β-chain (FIGS. 8c and 8d), TOP062-F8 (SEQ ID No: 1588) was also shown to be effective at reducing CCR3 mRNA (FIG. 8a) and protein (FIG. 8b) expression levels. The cross-target inhibitory effect was not restricted to TOP062-F8 (SEQ ID No: 1588), and was also observed with additional AON sequences (TOP057 (SEQ ID No: 8) and TOP073 (SEQ ID No: 24)) targeting β-chain (FIG. 9a and FIG. 9b).

Example 7

Multiple Gene Knock-Down Effect of Combining Two AON Derived from the Nucleotide Sequences of Two Different Target Genes

[0201] This example relates to the effect of the combination of specific AONs on β-chain and CCR3 gene expression. The effects of combining two separate AONs on β-chain and CCR3 mRNA expression in TF-1 cells expressing both receptors endogenously was assessed (FIG. 10). Each AON was transfected into cells singly or in combination. Cells were analyzed for mRNA or protein expression 24 hours post-transfection. The combination of TOP030-F2 (SEQ ID No: 1600) and TOP062-F8 (SEQ ID No: 1588) was demonstrated to be significantly more effective at decreasing CCR3 mRNA (FIG. 10a) and protein (FIG. 10b) expression levels compared to TOP030-F2 (SEQ ID No: 1600) alone. Similarly, the combination of a lower concentration of TOP062-F8 (SEQ ID No: 1588) relative to concentration of TOP030-F2 (SEQ ID No: 1600) exhibited a strong synergistic effect on the expression levels of β-chain mRNA (FIG. 10c) and protein (FIG. 10d) compared to TOP062-F8 (SEQ ID No: 1588) alone.

Example 8

Antisense Efficacy in a Rat Model of Allergen-Induced Airway Inflammation

[0202] This example relates to the enhanced efficacy of AON targeting the rat β-chain and rat CCR3 when FANA modifications are incorporated into the chemistry of the AON in vitro and in an in vivo model of allergic asthma in rats. Table 4 describes the compositions of AONs targeting the rat β-chain and rat CCR3 and modification with FANA residues. In FIG. 8, NIH 3T3 cells, engineered to transiently express the rat CCR3 mRNA, were transfected with a rat CCR3-specific AON (unmodified DNA with phosphorothioate linkage (TOP007 (SEQ ID No: 1628)) or incorporating FANA-modified nucleotides (TOP007-F8) (SEQ ID No: 1629) as indicated), and analyzed 24 hours post-transfection. The results showed that modification of TOP007 (SEQ ID No: 1628) sequence with FANA monomers (TOP007-F8 (SEQ ID No: 1629)) enhanced the efficacy of the AON with respect to inhibition of target mRNA expression, clearly showing an advantage of this modification for AON activity (FIG. 11).

[0203] The enhanced activity of FANA-modified AONs targeting rat β-chain and rat CCR3 was also demonstrated in an in vivo model of allergic asthma in Brown Norway (BN) rats. In this model of asthma, BN rats are challenged with ovalbumin (OVA) 14 days following sensitization, resulting in a marked influx of eosinophils in the lungs of the animals (FIG. 12). Eosinophils are a key cell underlying the allergic response in asthma. When BN rats were treated prior to challenge with 50 μg of a combination (ratio 1:1 w/w) of one unmodified AON targeting rat β-chain (TOP006 (SEQ ID No: 1626)) and one unmodified AON targeting rat CCR3 (TOP007 (SEQ ID No: 1628)), no significant reduction of the allergen-induced eosinophil influx was observed (FIG. 12). However, when sensitized BN rats were treated with 50 μg of a combination (ratio 1:1 w/w) of FANA-containing AONs (TOP006-F2 (SEQ ID No: 1627) and TOP007-F8 (SEQ ID No: 1629)), the allergen-induced eosinophil influx to the lung was reduced by 60% (FIG. 12).

Example 9

Macrophage Influx into the Lungs Following Chronic Delivery of 2'F-ANA Modified AONs

[0204] The example relates to the relative reduction in infiltration of alveolar macrophages following chronic dosing administration of FANA-modified AONs for 14 consecutive days in rodents and monkeys. FIG. 13 shows the percentage incidence of alveolar macrophages in the lungs of rodents (mice and rats) and of monkeys following chronic dosing of FANA modified AONs (TPI 1100) and of non-2'F-ANA modified AONs (TPI ASM8 (TOP004 (SEQ ID NO: 1630) and TOP005 (SEQ ID NO: 1631)). Lung histology was assessed 24 h following the last AON exposure (Day 15). Results indicated that animals receiving FANA modified AONs (TPI 1100 (TOP1572 (SEQ ID NO: 1632) and TOP1731 (SEQ ID NO:1633), IC₅₀ ˜1 mg/kg) had a lower incidence of alveolar macrophages compared to animals receiving non-2'F-ANA-containing AONs (TPI ASM8, IC₅₀ ˜0.1 mg/kg), and was species-independent (rodent or primate).

Example 10

Efficacy of 2-Amino-2'-Deoxyadenosine-Containing AON Sequences at Reducing β-Chain mRNA Expression

[0205] This example relates to the efficacy of β-chain-specific AONs incorporating 2-amino-2'-deoxyadenosine (DAP) modifications in the chemistry of the AON. Table 3c describes the compositions of AON modified with DAP residues. The potency of some selected sequences is demonstrated in FIG. 14 which shows the reduction in gene expression in vitro following transfection with indicated AONs in 293-βc-GFP cells. Specificity of the AON sequences was assessed by comparing their efficacy at reducing β-chain mRNA expression levels compared to an irrelevant AON sequence (TOP4005 (SEQ ID No: 1784)).

Example 11

Efficacy of miRNA Mimic Sequences at Reducing β-Chain mRNA and Protein Expression

[0206] In addition to AON sequences and siRNA, miRNA mimic molecules were designed (Table 7) and tested for their efficacy at reducing β-chain mRNA and protein expression (FIG. 15). FIG. 15a shows the efficacy of some selected miRNA mimic sequences at reducing β-chain mRNA levels in TF-1 cells compared to non-transfected cell controls (Control NT). In line with the mechanism of action of miRNA, no effect on β-chain mRNA levels were measured. The inhibitory activity of miRNA on β-chain protein expression was also analyzed by fluorescence activated cell sorting (FACS). FIG. 15b shows that TF-1 cells had dose-dependent decreases in levels of β-chain protein expression following transfection with specific miRNA and overnight incubation compared to untransfected control cells.

[0207] All references cited are incorporated by reference herein. Although preferred embodiments of the invention have been described herein, it will be understood by those skilled in the art that variations may be made thereto without departing from the spirit of the invention or the scope of the appended claims.

TABLE-US-00001 TABLE 1a Seq AON AON sequence ID ID (5'-3') Activity 1 TOP050 gctggtgtagtcgttgtagcag <20% 2 TOP051 gcaggtgatgtggctggtgtag <20% 3 TOP052 ggctccaggaggtcctcattc <20% 4 TOP053 ggctgaccagggcatgtcatc <20% 5 TOP054 ctcaggaggctggacatgctg <20% 6 TOP055 ggccacactccaggtcagc 20-40% 7 TOP056 ccacctccttcctcacctc <20% 8 TOP057 gaccgagctggccacctcc 20-40% 9 TOP058 ctgtctccatccttggtcac 20-40% 10 TOP059 gtcttgctgtccttccacgtgg 20-40% 11 TOP060 ctcactccactcgctccagatc 20-40% 12 TOP061 tcctctatggtgagaggtgac <20% 13 TOP062 ctctccacttccacggcctg >40% 14 TOP063 cagaggccactccagggtcctc 20-40% 15 TOP064 ggttcttgatctcaggaccg 20-40% 16 TOP065 agccgcttgtagaccacctc 20-40% 17 TOP066 tggcctgggaggtgttggag <20% 18 TOP067 tcctgagagccgagaacctg 20-40% 19 TOP068 ctccacttgctgggacgtcc 20-40% 20 TOP069 ctggagtcgtgtcaggccca <20% 21 TOP070 agagggaccagttgcacctg <20% 22 TOP071 cggccttctctccacttcca 20-40% 23 TOP072 ctcagtgtccccagagctca <20% 24 TOP073 tccactggccagcccaggac 20-40% 25 TOP074 ttggagggagctccacatag <20% 26 TOP075 ggattgttccttggtgacct <20% 27 TOP076 tggtctaggttcttgatctc <20% 28 TOP077 aagagtcctgaagccgcttgt >40% 29 TOP078 aggaggatggctgcgtcctc <20% 30 TOP079 gcatgaggtgctctggcc <20% 31 TOP080 gccacgtaggtgctgctg 20-40% 32 TOP081 gccaggcgggtccgtactc <20% 33 TOP082 tactcgggccacgtaggt 20-40% 34 TOP083 acctctgggctccacttg 20-40% 35 TOP084 cctggctgggagtcccagcaa <20% 36 TOP085 gggctgggcctcatccc <20% 37 TOP086 gaagcactccaggttctg 20-40% 38 TOP087 catctccctggtcagctctg <20% 39 TOP088 ggccagcaccatctccctgg <20% 40 TOP089 gcagcccctgggccagcacc <20% 41 TOP090 gccatggagagcagcccctg <20% 42 TOP091 ggccagcagggccatggaga <20% 43 TOP092 cccagcacagggccagcagg <20% 44 TOP093 aggctgcgctcccagcacag <20% 45 TOP094 tgcccctgccaggctgcgct <20% 46 TOP095 tggtttcttctgcccctgcca <20% 47 TOP096 cgttgtagcagcgcagggtc <20% 48 TOP097 cccacctgcaggtgatgtgg <20% 49 TOP098 tgggtgtctgcccacctgca <20% 50 TOP099 ctgggcatcctgggtgtctg <20% 51 TOP100 tgacgagccgctgggcatcc <20% 52 TOP101 agggtcacgttgacgagccg <20% 53 TOP102 ccggcgaatgagggtcacgt 20-40% 54 TOP103 cctcattcacccggcgaatg 20-40% 55 TOP104 ggacactggctccaggaggt 20-40% 56 TOP105 tgaggtcacaggacactggc <20% 57 TOP106 atgtcatcactgaggtcaca <20% 58 TOP107 gggggcaggctgaccagggc <20% 59 TOP108 cagcggggatgggggcaggc <20% 60 TOP109 cctgggcacgcagcggggat <20% 61 TOP110 tgacacatctcctgggcacg <20% 62 TOP111 tggcagggaatgacacatctc <20% 63 TOP112 gacaaaactctggcagggaa 20-40% 64 TOP113 cgtcagtgacgacaaaactct <20% 65 TOP114 aagtagtcaacgtcagtgac <20% 66 TOP115 ttggaatgagaagtagtcaa <20% 67 TOP116 gcctgtctggttggaatgag <20% 68 TOP117 gtgcccagaggcctgtctgg <20% 69 TOP118 ggtgagccgggtgcccagag <20% 70 TOP119 tcagagtgacggtgagccgg <20% 71 TOP120 acatgctgggtcagagtgac 20-40% 72 TOP121 ccctgggctcaggaggctgg <20% 73 TOP122 atctgcaggtccctgggctca <20% 74 TOP123 gtcggtgctgatctgcaggt <20% 75 TOP124 agtggtcctggtcggtgctg <20% 76 TOP125 gtcagcaggaagtggtcctg <20% 77 TOP126 tcccaagggccacactccag <20% 78 TOP127 ctctggggactcccaagggcca 20-40% 79 TOP128 caaccagtggctctggggac <20% 80 TOP129 cctggggacaaccagtgg <20% 81 TOP130 aactccagatcccctgggga <20% 82 TOP131 ccacctcaaactccagatcc n.d. 83 TOP132 gcctcactccactcgctcca 20-40% 84 TOP133 ccaggagcgcgcctcactcc <20% 85 TOP134 actcggtgtcccaggagcgc <20% 86 TOP135 ggcagcaccgactcggtgtc 20-40% 87 TOP136 cacccacataggcagcaccg 20-40% 88 TOP137 tgagggccagcacccacata 20-40% 89 TOP138 aagatcacgatgagggccag 20-40% 90 TOP139 gatggtgaggaagatcacga <20% 91 TOP140 ggagcacagcgatggtgagg <20% 92 TOP141 cggagggccaggagcacagc <20% 93 TOP142 gccacagaagcggagggcca <20% 94 TOP143 acccgtagatgccacagaag >40% 95 TOP144 cgcagcctgtacccgtagat 20-40% 96 TOP145 ccactttctgcgcagcctgt >40% 97 TOP146 tcttctcctcccactttctg <20% 98 TOP147 gggttggggatcttctcctc <20% 99 TOP148 gctcttgctggggttgggga <20% 100 TOP149 ggaacaggtggctcttgctg <20% 101 TOP150 ctcccgttctggaacaggtg 20-40% 102 TOP151 aagctctgcgctcccgttct <20% 103 TOP152 ctgggggccaaagctctgcg <20% 104 TOP153 gacatgctgcctgggggcca 20-40% 105 TOP154 agtgaaggccgacatgctgc 20-40% 106 TOP155 gactcccgctagtgaaggcc >40% 107 TOP156 tggtgtgggggactcccgct <20% 108 TOP157 ccacggcccctggtgtgggg n.d. 109 TOP158 agcggctgccccacggcccc <20% 110 TOP159 agctcagggaagcggctgcc n.d. 111 TOP160 caccccctccagctcaggga 20-40% 112 TOP161 ctacagggaacaccccctcc n.d. 113 TOP162 tccccgaatcctacagggaa n.d. 114 TOP163 cacctcgctgtccccgaatc <20% 115 TOP164 tgagaggtgacacctcgctg 20-40% 116 TOP165 atgcttggggtcctctatgg <20% 117 TOP166 gatcacagacatgcttgggg <20% 118 TOP167 ccagatggtggatcacagac 20-40% 119 TOP168 cgtgtcaggcccagatggtg <20% 120 TOP169 agatctgaggcagctggagt 20-40% 121 TOP170 ctctgtgggtagatctgagg <20% 122 TOP171 tggggggctgctctgtgggt <20%

123 TOP172 ggctgggggctggggggctg <20% 124 TOP173 aggcgggcctggctgggggc <20% 125 TOP174 gggaggcggcaggcgggcct <20% 126 TOP175 tcaggtgtgtgggaggcggc <20% 127 TOP176 agcctgtttctcaggtgtgt <20% 128 TOP177 caaagctggaagcctgtttc >40% 129 TOP178 ccattgaagtcaaagctgga >40% 130 TOP179 caggtagggcccattgaagt <20% 131 TOP180 ggggcggccccaggtagggc <20% 132 TOP181 gagcggctgtggggcggccc <20% 133 TOP182 gtcaggtagggagcggctgt <20% 134 TOP183 ggcccaggatgtcaggtagg <20% 135 TOP184 ggctccggctggcccaggat 20-40% 136 TOP185 ctcctgtgggggctccggct <20% 137 TOP186 ggctcccaccctcctgtggg <20% 138 TOP187 ggggacttctggctcccacc <20% 139 TOP188 ccctggaggtggggacttct <20% 140 TOP189 actccagggaccctggaggt 20-40% 141 TOP190 agacacaggtactccaggga 20-40% 142 TOP191 cccagcaggcagacacaggt <20% 143 TOP192 gcacctgccccccagcaggc >40% 144 TOP193 ctgggccagagggaccagtt 20-40% 145 TOP194 gtcccatcgcctgggccaga <20% 146 TOP195 gcctgtcccggtcccatcgc 20-40% 147 TOP196 ctggctcggccttctctc 20-40% 148 TOP197 ctgcagccccctggctc <20% 149 TOP198 agggagggactccctgcag <20% 150 TOP199 ggactccagggagggact <20% 151 TOP200 gcctcccccggactcca <20% 152 TOP201 caggaggggcagggcctccc <20% 153 TOP202 ggcccaagagcaggaggggc <20% 154 TOP203 tcccacccttggcccaagag 20-40% 155 TOP204 ggtcctgtcctcccaccctt <20% 156 TOP205 ctgtccttttggtcctgtcc 20-40% 157 TOP206 atagccacagggctgtcctt >40% 158 TOP207 ctcatgggtatagccacagg 20-40% 159 TOP208 tccccagagctcatgggtat 20-40% 160 TOP209 cataaccagaggccactcc 20-40% 161 TOP210 ggagacataaccagaggcca 20-40% 162 TOP211 gcagaggagacataacc 20-40% 163 TOP212 ggtgaataccaggtctgc 20-40% 164 TOP213 ctgagtttggggtgaatacc <20% 165 TOP214 acagacgaggcccctgagtt 20-40% 166 TOP215 actagggagacagacgaggc 20-40% 167 TOP216 cagagagggaactagggaga <20% 168 TOP217 aggggaggcccagagaggga <20% 169 TOP218 gtctggtctgaggggaggcc <20% 170 TOP219 taagctgggggtctggtctg <20% 171 TOP220 gcccaggacataagctgg >40% 172 TOP221 tccagggggtccactggcca <20% 173 TOP222 ggcctggggctccaggg <20% 174 TOP223 accctgacttcacagggcct 20-40% 175 TOP224 tcaaaccctgacttcacag 20-40% 176 TOP225 ccacatagccctcaaaccct 20-40% 177 TOP226 gccctcaattggagggagct <20% 178 TOP227 tgggggaccggccctcaat n.d. 179 TOP228 cttggtgacctgggggaccg n.d. 180 TOP229 ctcaggggggacaggattgt n.d. 181 TOP230 cttttggcctcaggggggac n.d. 182 TOP231 aggacagggcttttggcctc n.d. 183 TOP232 ccctgggttcaggacagg n.d. 184 TOP233 gccgggcgttcccctgggtt n.d. 185 TOP234 ggacacatctgccgggcgtt n.d. 186 TOP235 ggatgttggggacacatct n.d. 187 TOP236 tcgggctgtggggatgttgg n.d. 188 TOP237 aggaggccctcgggctgtg n.d. 189 TOP238 gctgcaggacaaggaggcc n.d. 190 TOP239 tcgcccacttgctgcaggac n.d. 191 TOP240 gaagcaatagtcgcccactt n.d. 192 TOP241 ggccggggaggaagcaatag n.d. 193 TOP242 ccgggccccaggccggggag n.d. 194 TOP243 cgagagagggccgggcccca n.d. 195 TOP244 tactccggagcgagagagg n.d. 196 TOP245 gaagaaggtttactccgg n.d. 197 TOP246 ggtcccggggaagaaggtt n.d. 198 TOP247 tctcaggaccgggtcccgg n.d. 199 TOP248 tgacttgaaaagcctggtct n.d. 200 TOP249 gggcttcttgacttgaa n.d. 201 TOP250 gcctggcctgggggcttct n.d. 202 TOP251 acctggggcacagcctggcct n.d. 203 TOP252 tgacgggcacctggggcac n.d. 204 TOP253 agagctgaatgacgggcacc n.d. 205 TOP254 ctagggctttgaagagctga n.d. 206 TOP255 actgagacaactagggctt n.d. 207 TOP256 cacagacatcactgagacaa n.d. 208 TOP257 ctggaggtcccacagacatc n.d. 209 TOP258 tctcaagggactggaggtcc n.d. 210 TOP259 tgacgtggggtctcaaggga n.d. 211 TOP260 tcagggctttgaagagctg n.d. 212 TOP261 tcctgctgcttcagggctt n.d. 213 TOP262 gacaggtagtcctgctgct n.d. 214 TOP263 agggggcagagacaggtag n.d. 215 TOP264 ttgacctcccaagggggcag n.d. 216 TOP265 ccaggcttgttgacctcc n.d. 217 TOP266 ctgaagccgcttgtagacc n.d. 218 TOP267 cgtcctcccaagagtcctg n.d. 219 TOP268 ttggagaggaggatggct n.d. 220 TOP269 ctctggccccagggtggc n.d. 221 TOP270 tgctgggcatgaggtgctct n.d. 222 TOP271 gccgagaacctggggcca n.d. 223 TOP272 gtcccagcaaacctctg n.d. 224 TOP273 cctcatcccctggctgg n.d. 225 TOP274 actccaggttctggggctg n.d. 226 TOP275 ccgtcaaagaagcactc n.d. 227 TOP276 gcacggcggccccgtcaa n.d. 228 TOP277 gagcagctgagcacggcggc n.d. 229 TOP278 ctcacctcccaggagcagc n.d. 230 TOP279 aaggagaccgagctggc n.d. 231 TOP280 gaataggccaaaggagaccg n.d. 232 TOP281 ctgggcttgtagaataggcc n.d. 233 TOP282 tgcatctgggctgggcttgt n.d. 234 TOP283 cttcctcccctgcatctgg n.d. 235 TOP284 gggagcactcttcctcc n.d. 236 TOP285 ctcagcactggggagcactc n.d. 237 TOP286 cgagcccctccctcagcact n.d. 238 TOP287 tggaggctgccgagcccctc n.d. 239 TOP288 gtgcctggtgtggaggctgc n.d. 240 TOP289 tctggcagtggtgcctggtg n.d. 241 TOP290 ggcacgggaatctggcagtg n.d. 242 TOP291 cgcggggtcgggcacgggaa n.d. 243 TOP292 ggccgtgggtcgcggggtcg n.d. 244 TOP293 acgatgtattggccgtgg n.d. 245 TOP294 ctgaacagagacgatgtatt n.d. 246 TOP295 cctccttggctgaacagag n.d. 247 TOP296 ttctctgccctccttgg n.d. 248 TOP297 gctctttatgtgtttctctg n.d.

249 TOP298 tgttcactgagctctttatg n.d. 250 TOP299 gccatctggatgttcactga n.d. 251 TOP300 ggatggaggggccatctgga n.d. 252 TOP301 tcacgttgagggatggagg n.d. 253 TOP302 tctccatccttggtcacgttg n.d. 254 TOP303 gcgcaggctgtagctgtctc n.d. 255 TOP304 attgtttcccagcgcaggct n.d. 256 TOP305 tcgcattttcattgtttccc n.d. 257 TOP306 tgtgttcgtatcgcattttc n.d. 258 TOP307 gtgtggtctatgtgttcgta n.d. 259 TOP308 gatctcaaatgtgtggtcta n.d. 260 TOP309 tcctgtactggatctcaa n.d. 261 TOP310 gccgtgtctttcctgtactg n.d. 262 TOP311 cttccacgtggccgtgtctt n.d. 263 TOP312 ggtctcggtcttgctgtc n.d. 264 TOP313 ggcgttctggagggtctcgg n.d. 265 TOP314 gccatgctgtgggcgttctgg n.d. 266 TOP315 gctggcagggccatgctgtg n.d. 267 TOP316 ggctccagggctggcagg n.d. 268 TOP317 acctggtggagggctccagg n.d. 269 TOP318 ctggcccagtacctggtgga n.d. 270 TOP319 gaccctcaccctggcccagt n.d. 271 TOP320 ggaggtcctgaccctcacc n.d. 272 TOP321 tagccggtgcgggaggtcct n.d. 273 TOP322 gatcccgttgtagccggtgc n.d. 274 TOP323 actcgctccagatcccgttg n.d. 275 TOP324 tcaacacacctccccaggcttg n.d. 276 TOP325 tgggggtctcaacacacctc n.d. 277 TOP326 tgtctaggcctgggggtctc n.d. 278 TOP327 ttcttctggagcctctaggc n.d. 279 TOP328 agaccagtcttcttctggag n.d. 280 TOP329 gtggtgggagagaccagtct n.d. 281 TOP330 aggcctctgtgtggtgggag n.d. 282 TOP331 tgcctcctccaggcctctgt n.d. 283 TOP332 tcctggcctctgcctcctcc n.d. 284 TOP333 gacctctccctcctggcctc n.d. 285 TOP334 aggctcttgggacctctcc n.d. 286 TOP335 ccatttcacaggctcttgg n.d. 287 TOP336 gccaggccagacccatttcac n.d. 288 TOP337 cagctgggagccaggccaga n.d. 289 TOP338 tgttcctgcccagctgggag n.d. 290 TOP339 tgaagtcctgtgttcctgcc n.d. 291 TOP340 cttagtgtcctgaagtcctg n.d. 292 TOP341 tgacagggtccttagtgtcc n.d. 293 TOP342 gccatgggcatgacagggtc n.d. 294 TOP343 gtgggtgctggccatgggca n.d. 295 TOP344 accagcactggtgggtgctg n.d. 296 TOP345 acaggcaggcaccagcactg n.d. 297 TOP346 tcagctctggacaggcaggc n.d. 298 TOP347 atacctctgtgtggtgggag n.d. 299 TOP348 ggccatacctctgtgtggt n.d. 300 TOP349 ctggacgccgggccatacctc n.d. 301 TOP350 ggcctgcagaaggagatgtc n.d. 302 TOP351 tcctccaggcctgcagaagg n.d. 303 TOP352 ctctgcctcctccaggcctg n.d. 304 TOP353 caccttctgcccctgccagg n.d. 305 TOP354 ccacgggactcaccttctgcc n.d. 306 TOP355 ggagccacgggactcacctt n.d. 307 TOP356 ttctgacaagaggggtaga n.d. 308 TOP357 ggatggtttctgacaagag n.d. 309 TOP358 ctgcagcgggatggtttctg n.d. 310 TOP359 cactcattcacccggcg n.d. 311 TOP360 gcatcactcactcattcacc n.d. 312 TOP361 ccagcatcactcactca n.d. 313 TOP362 tccctgttgggagaggacac n.d. 314 TOP363 caggaggtccctgttgggag n.d. 315 TOP364 ctggctccaggaggtccctg n.d. 316 TOP365 caccatgctgggtcagagtg n.d. 317 TOP366 cctcaccatgctgggtc n.d. 318 TOP367 ccccagcccctcaccat n.d. 319 TOP368 ggactggaggggaggaagtg n.d. 320 TOP369 ggaggctggactggagg n.d. 321 TOP370 ggctcaggaggctggactg n.d. 322 TOP371 tacctcccaagagtcctg n.d. 323 TOP372 cgtggttcctacctcccaag n.d. 324 TOP373 ctggccgtggttcctacctc n.d. 325 TOP374 gtcctgtcaggagacagtgg n.d. 326 TOP375 tggctgcgtcctgtcaggag n.d. 327 TOP376 caggacgcagccatcctcc n.d. 328 TOP377 tacctggctgggagtcc n.d. 329 TOP378 tggcaacattacctggctgg n.d. 330 TOP379 ggctctggcaacattacctg n.d. 331 TOP380 cccctgggttggagacaggt n.d. 332 TOP381 gcctcatcccctgggttgga n.d. 333 TOP382 ggctgggcctcatcccctg n.d. 334 TOP383 caccctgcatctgggctgg n.d. 335 TOP384 gatgctcaccctgcatctg n.d. 336 TOP385 aaaaagatgctcaccct n.d. 337 TOP386 tccctgaggagcacagcag n.d. 338 TOP387 ctcttcctccctgaggagc n.d. 339 TOP388 ggagcactcttcctccctg n.d. 340 TOP389 cactgttcactgagctctt n.d. 341 TOP390 aactcactgttcactgag n.d. 342 TOP391 gctaggagcaaactcactgt n.d. 343 TOP392 ggactggagggagggaagct n.d. 344 TOP393 gccatctggactggagggag n.d. 345 TOP394 tggaggggccatctggactg n.d. 346 TOP395 caccttccacgtggccgtgt n.d. 347 TOP396 cctcaccttccacgtgg n.d. 348 TOP397 ggcaaaggccctcacctt n.d. 349 TOP398 gtcctgtgggttggcactga n.d. 350 TOP399 tcttgctgtcctgtgggttg n.d. 351 TOP400 gtctcggtcttgctgtcctg n.d. 352 TOP401 tacccgactcggtgtcc n.d. 353 TOP402 gccttcacctacccgactcg n.d. 354 TOP403 ctccagccttcacctacccg n.d. 355 TOP404 gcacttccagcagccgg n.d. 356 TOP405 cataggcagcacttccagc n.d. 357 TOP406 ccacataggcagcactt n.d. 358 TOP407 cacctgtacccgtagatgcc n.d. 359 TOP408 gtcccctcacctgtacccgt n.d. 360 TOP409 ccacagagtcccctcacctg n.d. 361 TOP410 agcctggaagacaccacgga n.d. 362 TOP411 ttctgcgcagcctggaagac n.d. 363 TOP412 ccactttctgcgcagcctg n.d. 364 TOP413 tacctggaacaggtggctct n.d. 365 TOP414 cagttcctacctggaacagg n.d. 366 TOP415 tcgcagccagttcctacctg n.d. 367 TOP416 gttctgcaagagcagagac n.d. 368 TOP417 gcgctcccgttctgcaagag n.d. 369 TOP418 gctctgcgctcccgttctg n.d. 370 TOP419 cacccctccagctcagg n.d. 371 TOP420 gagcccactcacccctccag n.d. 372 TOP421 tccacgagcccactcacccc n.d. 373 TOP422 accctgtgggaagaaaatgg n.d.

374 TOP423 ggaacaccctgtgggaag n.d. 375 TOP424 tcctacagggaacaccctg n.d. 376 TOP425 gtctcaacacacctccc n.d. 377 TOP426 gcctgggggtctcaacacac n.d. 378 TOP427 gtctaggcctgggggtctca n.d. 379 TOP428 agccctgctcctggacgccgg n.d. 380 TOP429 ccacccctcagccctgctcc n.d. 381 TOP430 ctgctctgaccccacccctc n.d. 382 TOP431 tgcccctccccttccacgtg n.d. 383 TOP432 gtcagcagtgagctgcccctcc n.d. 384 TOP433 aggagatgtcagcagtgagc n.d. 385 TOP434 agtgggtgggagccacgg n.d. 386 TOP435 agggacagggaagtgggtgg n.d. 387 TOP436 gcagtgaggacagggacagg n.d. 388 TOP437 ctgcagggacccttgtcacc n.d. 389 TOP438 ctctctttcctgcagggacc n.d. 390 TOP439 agggggtcacctctctttcc n.d. 391 TOP440 gaggggtagaagggggtcac n.d. 392 TOP441 gtggcccctgcccccagcat n.d. 393 TOP442 gcccctgcccgtggcccctg n.d. 394 TOP443 ggacgtcgtagcccctgcc n.d. 395 TOP444 agggtgtatgggtatcactg n.d. 396 TOP445 ggcttagcccagggtgtatg n.d. 397 TOP446 gagaggacacggcttagcc n.d. 398 TOP447 ccgggcagggcccccagc n.d. 399 TOP448 ggaaaccaagccccgggcag n.d. 400 TOP449 tgtccacacaggaaaccaag n.d. 401 TOP450 ccgctggggggcagtcagg n.d. 402 TOP451 aagggctggaccgctggg n.d. 403 TOP452 aagggcacctaagggctgga n.d. 404 TOP453 ggaggaagtgaagggcacct n.d. 405 TOP454 ggcagagctggccgtggt n.d. 406 TOP455 ccttcgggctggggcagagc n.d. 407 TOP456 gctgcccatcccttcgggct n.d. 408 TOP457 gtgctggaggaggggtgctg n.d. 409 TOP458 gagacagtgggtgctggagg n.d. 410 TOP459 gcatttcctgggctctggca n.d. 411 TOP460 ccaccacggggcatttcctg n.d. 412 TOP461 gcctgccctcccaccacgg n.d. 413 TOP462 tccgtcattcatccctcccat n.d. 414 TOP463 cctcatgtactccgtcattc n.d. 415 TOP464 ggagacaggtcctcatgtac n.d. 416 TOP465 gaggggatggagaaaaaaga n.d. 417 TOP466 aagaggaggggaggggatgg n.d. 418 TOP467 gagcaaggccaagaggagg n.d. 419 TOP468 ggagggaggagagcttagg n.d. 420 TOP469 agggcacacgggagggagga n.d. 421 TOP470 agggagagggagggcacacg n.d. 422 TOP471 agctgagggcagggagagg n.d. 423 TOP472 agcacagcagagctgagggc n.d. 424 TOP473 ccacagcgggctaggagca n.d. 425 TOP474 cagaccatccccacagcgg n.d. 426 TOP475 gtgctggtcccagaccatcc n.d. 427 TOP476 gtcatcatacccaccctcca n.d. 428 TOP477 ttcaggagagtcatcatacc n.d. 429 TOP478 agggaagctttcaggagagt n.d. 430 TOP479 ctcccctccctgggcaaagg n.d. 431 TOP480 ccagtgtttctcccctcc n.d. 432 TOP481 tcccgccctccccagtgtt n.d. 433 TOP482 ccgtgggagcagctgcaaat n.d. 434 TOP483 tggcccggtgcccgtgggag n.d. 435 TOP484 ggtgaggcctggcccggtg n.d. 436 TOP485 ttggcactgagggtgaggcc n.d. 437 TOP486 aagctctggactccagcctt n.d. 438 TOP487 tcctggccagaagctctgga n.d. 439 TOP488 tatgagctggtcctggccag n.d. 440 TOP489 gaaatcgacctcagggcagg n.d. 441 TOP490 atctgggcgggaaatcgacctc n.d. 442 TOP491 gaatgtcagcatctgggcgg n.d. 443 TOP492 ggagaaagaggaatgtcagc n.d. 444 TOP493 cagcagccggggagaaagag n.d. 445 TOP494 acctccagccccacagagtc n.d. 446 TOP495 ctcggctgccacctccagcc n.d. 447 TOP496 cctctggggtctcggctgcc n.d. 448 TOP497 atcagagacctcatggccag n.d. 449 TOP498 ggtgacagccatcagagacc n.d. 450 TOP499 acaccacggaggtgacagcc n.d. 451 TOP500 actccgcccctcgcagccag n.d. 452 TOP501 agaagcccccactccgcc n.d. 453 TOP502 gcaggaacagagaagccccc n.d. 454 TOP503 gtgagcatcaggaggtccga n.d. 455 TOP504 atttgggccggtgagcatca n.d. 456 TOP505 gagcagagacatttgggccg n.d. 457 TOP506 tcaggagtgatccacgagcc n.d. 458 TOP507 accccaaaggtcaggagtga n.d. 459 TOP508 ccgtatgaaccccaaagg n.d. 460 TOP509 gatccgggtcaggcacaag n.d. 461 TOP510 ctgggcagatgatccgggtca n.d. 462 TOP511 tgggaccaccctgggcagat n.d. 463 TOP512 gcagaagagttgggaccacc n.d. 464 TOP513 aagaaaatgggcagaagagt n.d. 465 TOP514 ccttgcctgtctaggcct n.d. 466 TOP515 cctctccatccccttgcct n.d. 467 TOP516 ggaaggcaagccctctccat n.d. 468 TOP517 tccccttgcctgtctaggcc n.d. 469 TOP518 gccctctccatccccttgcc n.d. 470 TOP519 ggaaggcaagccctctcca n.d. 471 TOP520 tcaggcgggagggaaggcaa n.d. 472 TOP521 ctgaggaaggtcaggcggga n.d. 473 TOP522 gcagaaatgactgaggaagg n.d. 474 TOP523 ccttggctttgcagaaatga n.d. 475 TOP524 ggaggctgccccttggctt n.d. 476 TOP525 taccttgacaggaggctgcc n.d. 477 TOP526 ggcctctagctaccttgaca n.d. 478 TOP527 tcctttcccaggcctctagc n.d. 479 TOP528 caaggctatctcctttccca n.d. 480 TOP529 ggccggagcaaggctatc n.d. 481 TOP530 gaaggtcaagggggccggag n.d. 482 TOP531 gtgatttgctgaaggtcaag n.d. 483 TOP532 agggagagaagtgatttgct n.d. 484 TOP533 gtgtgagcgcagggagagaa n.d. 485 TOP534 gtgtgtgtctgtgtgagcgc n.d. 486 TOP535 acgtgtgtgtgtgtgtgtct n.d. 487 TOP536 gtgtgcatgtacgtgtgtgt n.d. 488 TOP537 caggaaaaatgtgtgcatgt n.d. 489 TOP538 gttaacctgacaggaaaaat n.d. 490 TOP539 ctacaaataagttaacctga n.d. 491 TOP540 aatgcagaacctacaaataa n.d. 492 TOP541 aagttctaataatgcagaac n.d. 493 TOP542 tatatctagaaagttctaat n.d. 494 TOP543 atggaatgagtatatctaga n.d. 495 TOP544 tgagggggagatggaatgag n.d. 496 TOP545 attaaaaaaatgagggggag n.d. 497 TOP546 aggaaacctgattaaaaaaat n.d. 498 TOP547 ggcaaaagcaaggaaacctg n.d. 499 TOP548 gaagaaaaatggcaaaagca n.d.

500 TOP549 gaaaaaagaaggaagaaaaatg n.d. 501 TOP550 taaatcagtgaaaaaagaag n.d. 502 TOP551 actctcataataaatcagtg n.d. 503 TOP552 cctcagccccactctcataa n.d. 504 TOP553 tcagctcagacctcagcc n.d. 505 TOP554 ctgataaggctcagctcaga n.d. 506 TOP555 gcatctcagtctgataaggc n.d. 507 TOP556 acaaccagccgcatctcagt n.d. 508 TOP557 agtcctcaacacaaccagcc n.d. 509 TOP558 agcccacacaagtcctcaac n.d. 510 TOP559 ggacaggcagcccacaca n.d. 511 TOP560 agcgactgccggggacaggc n.d. 512 TOP561 catgtgcatcagcgactgcc n.d. 513 TOP562 agaatcatgtcatgtgcatc n.d. 514 TOP563 cacccagatgagaatcatgt n.d. 515 TOP564 ccacctctgcacccagatg n.d. 516 TOP565 cctggtgcctcccacctctg n.d. 517 TOP566 cgggtgcccacctggtgcct n.d. 518 TOP567 ctaacccccacgggtgccca n.d. 519 TOP568 cttccaagccctaaccccca n.d. 520 TOP569 ctgtgccactcttccaagcc n.d. 521 TOP570 gtgcccagtcctgtgccact n.d. 522 TOP571 ctcactgagcgtgcccagtc n.d. 523 TOP572 ttccctgagcctcactgagc n.d. 524 TOP573 ctagtctgaattccctgagc n.d. 525 TOP574 acaatcgaggctagtctgaa n.d. 526 TOP575 tctcggagtgacaatcgagg n.d. 527 TOP576 catgcccatttctcggagtg n.d. 528 TOP577 ccaataccatgcccatt n.d. 529 TOP578 gcccccccgacccccaatac n.d. 530 TOP579 ccttgcaccgcccccccga n.d. 531 TOP580 tcatgtgcgtcccttgcacc n.d. 532 TOP581 aacagtctctcatgtgcgt n.d. 533 TOP582 agaagctcccaaacagtctc n.d. 534 TOP583 agggctccccagaagctcc n.d. 535 TOP584 gacaactagcagggctcc n.d. 536 TOP585 acatcactgagacaactagc n.d. 537 TOP586 ggtcccacagacatcactga n.d. 538 TOP587 agggactggaggtcccacag n.d. 539 TOP588 tggggtctcaagggactgga n.d. 540 TOP589 ctacatgacgtggggtctca n.d. 541 TOP590 gttaacttctctacatgacg n.d. 542 TOP591 cacttgggccgttaacttct n.d. 543 TOP592 gcctgcccaccacttgggcc n.d. 544 TOP593 ggtcccgccagcctgcccac n.d. 545 TOP594 atgttccccaggtcccgcca n.d. 546 TOP595 tcctctcctgatgttcccca n.d. 547 TOP596 ggctctggactcctctcctg n.d. 548 TOP597 agtagacgtgggctctggac n.d. 549 TOP598 acttttccgcagtagacgtg n.d. 550 TOP599 gtttcccctgacttttccgc n.d. 551 TOP600 ttgtttggcagtttcccctg n.d. 552 TOP601 gcattttcctttgtttggca n.d. 553 TOP602 tgcctttggggcattttcct n.d. 554 TOP603 aagcatatatgcctttgg n.d. 555 TOP604 caaaggccctaaagcatata n.d. 556 TOP605 ccatttggaccaaaggccct n.d. 557 TOP606 gccacccgggccatttggac n.d. 558 TOP607 tggaagagtggccacccgg n.d. 559 TOP608 ctggtctatctggaagagtg n.d. 560 TOP609 ggagagttgcctggtctatc n.d. 561 TOP610 ccggtgggagggagagttgc n.d. 562 TOP611 tcatctgtggccggtgggag n.d. 563 TOP612 cagcagcccctcatctgtgg n.d. 564 TOP613 aggcatagatcagcagcc n.d. 565 TOP614 gtgcaggcccaggcatagat n.d. 566 TOP615 ataatccctggtgcaggcc n.d. 567 TOP616 taaaagaaccataatccctg n.d. 568 TOP617 aggcaaagatttaaaagaacc n.d. 569 TOP618 gtatctgaaaggcaaagatt n.d. 570 TOP619 tatttttcctgtatctgaa n.d. 571 TOP620 ttaatgccattatttttcct n.d. 572 TOP621 ttaaagcaatttaatgccat n.d. 573 TOP622 ataatgcaaattaaagcaat n.d. 574 TOP623 gataactaaaataatgcaa n.d. 575 TOP624 gtgcaaactggataactaa n.d. 576 TOP625 ataaaaatatgtgcaaactg n.d. 577 TOP626 taagatacctataaaaatat n.d. 578 TOP627 aatcgatgcctaagatacct n.d. 579 TOP628 aaaataccaatcgatgcc n.d. 580 TOP629 tggcccagttaaaaaatacc n.d. 581 TOP630 ttaatgggcttggcccagtt n.d. 582 TOP631 aagaaagaccttaatgggct n.d. 583 TOP632 cacccaacagaagaaagacc n.d. 584 TOP633 aatgatagcacccaacag n.d. 585 TOP634 acttaatcagaaaatgatag n.d. 586 TOP635 agtcaaaaagacttaatcag n.d. 587 TOP636 gtatgtcaatagtcaaaaag n.d. 588 TOP637 gtgaaagactgtatgtcaat n.d. 589 TOP638 tccaccatctgtgaaagact n.d. 590 TOP639 ggaaaaacactccaccatct n.d. 591 TOP640 cagatttgggggaaaaacac n.d. 592 TOP641 agacaaacaacagatttgg n.d. 593 TOP642 caacattataagacaaacaa n.d. 594 TOP643 acctcatatacaacattata n.d. 595 TOP644 acaccataaaacctcatata n.d. 596 TOP645 tcatattcatacaccataa n.d. 597 TOP646 acagaagcattcatattcat n.d. 598 TOP647 gtttgacattacagaagcat n.d. 599 TOP648 ctagggatctgtttgacatt n.d. 600 TOP649 aaggagtttactagggatct n.d. 601 TOP650 aagtgaagaaggagttta n.d. 602 TOP651 atctgacagtaaaagtgaag n.d. 603 TOP652 acctttgtaaatctgacagt n.d. 604 TOP653 caatgggaggacctttgtaa n.d. 605 TOP654 cactgctttgcaatgggagg n.d. 606 TOP655 ttaggacaaacactgctttg n.d. 607 TOP656 aatatataaattaggacaa n.d. 608 TOP657 ctagaaaaacaatatataa n.d. 609 TOP658 acaaaatgaactagaaaaac n.d. 610 TOP659 agttggaaacacaaaatgaa n.d. 611 TOP660 ttacatgaaaagttggaaac n.d. 612 TOP661 aattaaaattttacatgaa n.d. 613 TOP662 attcaaaaataattaaaatt n.d. 614 TOP663 acatccacacattcaaaaat n.d. 615 TOP664 cctcagtctcacatccacac n.d. 616 TOP665 ccaaaaggcacctcagtctc n.d. 617 TOP666 aatttcagtaccaaaaggca n.d. 618 TOP667 atggaaaaagaatttcagta n.d. 619 TOP668 cttcaggtacatggaaaaag n.d. 620 TOP669 aagtaacacttcaggtac n.d. 621 TOP670 cctatatcacaaaagtaaca n.d. 622 TOP671 acaaggatttcctatatcac n.d. 623 TOP672 aagtatatatacaaggatt n.d. 624 TOP673 ggaccaataaagtatatat n.d.

625 TOP674 aggaagcctagggaccaata n.d. 626 TOP675 gtaacaaaataggaagccta n.d. 627 TOP676 agaaagcaaggtaacaaaat n.d. 628 TOP677 gatgccatagagaaagcaag n.d. 629 TOP678 caaaatggtggatgccatag n.d. 630 TOP679 gtagaacaatcaaaatggtg n.d. 631 TOP680 tatcataaaagtagaacaat n.d. 632 TOP681 tatgaaaacatatcataa n.d. 633 TOP682 cttaaccacttatgaaaaca n.d. 634 TOP683 agaatacttgcttaaccact n.d. 635 TOP684 aagtaacgagaatacttg n.d. 636 TOP685 atttaagagcaaaagtaacg n.d. 637 TOP686 atgaatagggatttaagagc n.d. 638 TOP687 cattgctgtaatgaatagg n.d. 639 TOP688 tgaccaccaacattgctgta n.d. 640 TOP689 tcattttctttgaccaccaa n.d. 641 TOP690 aagttgtttatcattttctt n.d. 642 TOP691 ttgaacattcaagttgttta n.d. 643 TOP692 ttcaggaccattgaacattc n.d. 644 TOP693 tgttatgtatttcaggacca n.d. 645 TOP694 actaaaatgttgttatgtat n.d. 646 TOP695 ttacaatgtactaaaatgt n.d. 647 TOP696 aggattctactttacaatgt n.d. 648 TOP697 ttatgaacagaggattctac n.d. 649 TOP698 atcttgttcattatgaacag n.d. 650 TOP699 acattggttcatcttgttca n.d. 651 TOP700 ttctaatccacattggttc n.d. 652 TOP701 ctcggacttctttctaatcc n.d. 653 TOP702 attaatatctcggacttc n.d. 654 TOP703 ggatattttggaattaatat n.d. 655 TOP704 aacaatgtctggatattttg n.d. 656 TOP705 ttccctttaacaatgtct n.d. 657 TOP706 ttattgcaattttttccctt n.d. 658 TOP707 acaaatattttattgcaatt n.d. 659 TOP708 ttttatgttacaaatattt n.d. 660 TOP709 gaccagttgcacctgccc n.d. 661 TOP710 ccacggcctgtcccggtc n.d. 662 TOP711 ggactccctgcagcccc n.d. 663 TOP712 aggggcagggcctccccc n.d. 664 TOP713 gccacagggctgtccttttg n.d. 665 TOP714 gccactccagggtcctcagtg n.d. 666 TOP715 accaggtctgcagaggag n.d. 667 TOP716 cgaggcccctgagtttgg n.d. 668 TOP717 ccaggacataagctgggg n.d. 669 TOP718 gcctggggctccaggggg n.d. 670 TOP719 ccacatagccctcaaacc n.d. 671 TOP720 ggacaggattgttccttg n.d. 672 TOP721 cgttcccctgggttcagg n.d. Lower case letters = DNA n.d. = not determined

TABLE-US-00002 TABLE 1b Seq ID Antisense Sequence CCR3 mRNA number ID (5'-3') Inhibition 673 TOP020 gtatctagtgaggttgtcat <20% 674 TOP021 ggtctcaactgtatctagtg <20% 675 TOP022 ccatcagtgctctggtatcagc <20% 676 TOP023 ggtacatcaccaccaccac <20% 677 TOP024 ggtcataattcggagcctcctg <20% 678 TOP025 gcttacacatgccatggcc <20% 679 TOP026 gctgctagcactgccagg <20% 680 TOP027 cctccagctatatactgtatcc <20% 681 TOP028 ggtccagatgcttgctcc 20-40% 682 TOP029 gcatgaccaggtccagatgc 20-40% 683 TOP030 cacctctgtcaccagcatg >40% 684 TOP031 gtacttccggaacctctctcc >40% 685 TOP032 ccacattgtagggtgtcca >40% 686 TOP033 agtgggagtaggcgatcacc <20% 687 TOP034 cgtagatcaccgggttcatg 20-40% 688 TOP035 ttccagcttctcactagga >40% 689 TOP036 tggtcattctcagagtgtgg <20% 690 TOP037 acagagctggttctttccag >40% 691 TOP038 gaatgggatgtatctgccca >40% 692 TOP039 ggatgtatctgcccaggtgc 20-40% 693 TOP040 caagtgcctgtggaagaagt >40% 694 TOP041 gcctgtggaagaagtggcgc 20-40% 695 TOP042 accaggtccagatgcttgct >40% 696 TOP043 attcaggaagagctgctagc <20% 697 TOP044 gtcgattgtcagcaggatta <20% 698 TOP045 atggaagggtgacgaggaag <20% Lower case letters = DNA

TABLE-US-00003 TABLE 2a SEQ ID Nos β-chain (anti- siRNA mRNA sense/ ID Antisense strand Inhib- sense) NUMBER Target sequence (5'-3') (5'-3') Sense strand (5'-3') ition 699/700 ¹siBc_1HP CTCCTTTGGCCTATTCTACAA UUGUAGAAUAGGCCAAAGGag CUUUUGGCCUAUUCUACAAtt >40% 701/702 ¹siBc_5HP AAGCATGTCTGTGATCCACCA UGGUGGAUCACAGACAUGCtt GCAUGUCUGUGAUCCACCAtt 20-40% 703/704 ¹siBc_6HP AAGGACAGCCCTGTGGCTATA UAUAGCCACAGGGCUGUCCtt GGACAGCCCUGUGGCUAUAtt 20-40% 705/706 ²siBc_2281 AAGGACAGCCCTGTGGCTATA UAUAGCCACAGGGCUGUCCUUtt AAGGACAGCCCUGUGGCUAUAtt 20-40% 707/708 ²siBc_1302 AATGCGATACGAACACATAGA UCUAUGUGUUCGUAUCGCAUUtt AAUGCGAUACGAACACAUAGAtt >40% 709/710 ²siBc_1191 AAGGAGGGCAGAGAAACACAT AUGUGUUUCUCUGCCCUCCUUtt AAGGAGGGCAGAGAAACACAUtt >40% 711/712 TOP5217 AACACAGGACTTCAGGACACTAA AGUGUCCUGAAGUCCUGUGdTdT CACAGGACUUCAGGACACUdTdT n.d. 713/714 TOP5218 TACAACGACTACACCAGCCACAT GUGGCUGGUGUAGUCGUUGdTdT CAACGACUACACCAGCCACdTdT n.d. 715/716 TOP5219 CAACGACTACACCAGCCACATCA AUGUGGCUGGUGUAGUCGUdTdT ACGACUACACCAGCCACAUdTdT n.d. 717/718 TOP5220 AACGACTACACCAGCCACATCAC GAUGUGGCUGGUGUAGUCGdTdT CGACUACACCAGCCACAUCdTdT n.d. 719/720 TOP5221 GACTACACCAGCCACATCACCTG GGUGAUGUGGCUGGUGUAGdTdT CUACACCAGCCACAUCACCdTdT n.d. 721/722 TOP5222 TACACCAGCCACATCACCTGCAG GCAGGUGAUGUGGCUGGUGdTdT CACCAGCCACAUCACCUGCdTdT n.d. 723/724 TOP5223 CACCAGCCACATCACCTGCAGGT CUGCAGGUGAUGUGGCUGGdTdT CCAGCCACAUCACCUGCAGdTdT n.d. 725/726 TOP5224 CAGCCACATCACCTGCAGGTGGG CACCUGCAGGUGAUGUGGCdTdT GCCACAUCACCUGCAGGUGdTdT n.d. 727/728 TOP5225 CACATCACCTGCAGGTGGGCAGA UGCCCACCUGCAGGUGAUGdTdT CAUCACCUGCAGGUGGGCAdTdT n.d. 729/730 TOP5226 CATCACCTGCAGGTGGGCAGACA UCUGCCCACCUGCAGGUGAdTdT UCACCUGCAGGUGGGCAGAdTdT n.d. 731/732 TOP5227 CACCTGCAGGTGGGCAGACACCC GUGUCUGCCCACCUGCAGGdTdT CCUGCAGGUGGGCAGACACdTdT n.d. 733/734 TOP5228 CAGGTGGGCAGACACCCAGGATG UCCUGGGUGUCUGCCCACCdTdT GGUGGGCAGACACCCAGGAdTdT n.d. 735/736 TOP5229 GGGCAGACACCCAGGATGC GCAUCCUGGGUGUCUGCCCdtdt GGGCAGACACCCAGGAUGCdtdt n.d. 737/738 TOP5230 CAGACACCCAGGATGCCCAGCGG GCUGGGCAUCCUGGGUGUCdTdT GACACCCAGGAUGCCCAGCdTdT n.d. 739/740 TOP5231 GATGCCCAGCGGCTCGTCAACGT GUUGACGAGCCGCUGGGCAdTdT UGCCCAGCGGCUCGUCAACdTdT n.d. 741/742 TOP5232 CAGCGGCTCGTCAACGTGACCCT GGUCACGUUGACGAGCCGCdTdT GCGGCUCGUCAACGUGACCdTdT n.d. 743/744 TOP5233 CAACGTGACCCTCATTCGCCGGG CGGCGAAUGAGGGUCACGUdTdT ACGUGACCCUCAUUCGCCGdTdT n.d. 745/746 TOP5234 AACGTGACCCTCATTCGCCGGGT CCGGCGAAUGAGGGUCACGdTdT CGUGACCCUCAUUCGCCGGdTdT n.d. 747/748 TOP5235 GACCCTCATTCGCCGGGTGAATG UUCACCCGGCGAAUGAGGGdTdT CCCUCAUUCGCCGGGUGAAdTdT n.d. 749/750 TOP5236 CCCTCATTCGCCGGGTGAA UUCACCCGGCGAAUGAGGGdtdt CCCUCAUUCGCCGGGUGAAdtdt n.d. 751/752 TOP5237 CATTCGCCGGGTGAATGAGGACC UCCUCAUUCACCCGGCGAAdTdT UUCGCCGGGUGAAUGAGGAdTdT n.d. 753/754 TOP5238 GAATGAGGACCTCCTGGAGCCAG GGCUCCAGGAGGUCCUCAUdTdT AUGAGGACCUCCUGGAGCCdTdT n.d. 755/756 TOP5239 AATGAGGACCTCCTGGAGCCAGT UGGCUCCAGGAGGUCCUCAdTdT UGAGGACCUCCUGGAGCCAdTdT n.d. 757/758 TOP5240 GAGGACCTCCTGGAGCCAGTGTC CACUGGCUCCAGGAGGUCCdTdT GGACCUCCUGGAGCCAGUGdTdT n.d. 759/760 TOP5241 GGACCTCCTGGAGCCAGTG CACUGGCUCCAGGAGGUCCdtdt GGACCUCCUGGAGCCAGUGdtdt n.d. 761/762 TOP5242 GACCTCCTGGAGCCAGTGTCCTG GGACACUGGCUCCAGGAGGdTdT CCUCCUGGAGCCAGUGUCCdTdT n.d. 763/764 TOP5243 GAGCCAGTGTCCTGTGACCTCAG GAGGUCACAGGACACUGGCdTdT GCCAGUGUCCUGUGACCUCdTdT n.d. 765/766 TOP5244 CAGTGTCCTGTGACCTCAGTGAT CACUGAGGUCACAGGACACdTdT GUGUCCUGUGACCUCAGUGdTdT n.d. 767/768 TOP5245 GACCTCAGTGATGACATGCCCTG GGGCAUGUCAUCACUGAGGdTdT CCUCAGUGAUGACAUGCCCdTdT n.d. 769/770 TOP5246 CCTCAGTGATGACATGCCC GGGCAUGUCAUCACUGAGGdtdt CCUCAGUGAUGACAUGCCCdtdt n.d. 771/772 TOP5247 CAGTGATGACATGCCCTGGTCAG GACCAGGGCAUGUCAUCACdTdT GUGAUGACAUGCCCUGGUCdTdT n.d. 773/774 TOP5248 GATGACATGCCCTGGTCAGCCTG GGCUGACCAGGGCAUGUCAdTdT UGACAUGCCCUGGUCAGCCdTdT n.d. 775/776 TOP5249 GACATGCCCTGGTCAGCCTGCCC GCAGGCUGACCAGGGCAUGdTdT CAUGCCCUGGUCAGCCUGCdTdT n.d. 777/778 TOP5250 GCCCAGGAGATGTGTCATT AAUGACACAUCUCCUGGGCdtdt GCCCAGGAGAUGUGUCAUUdtd n.d. 779/780 TOP5251 CAGGAGATGTGTCATTCCCTGCC CAGGGAAUGACACAUCUCCdTdT GGAGAUGUGUCAUUCCCUGdTdT n.d. 781/782 TOP5252 GAGATGTGTCATTCCCTGCCAGA UGGCAGGGAAUGACACAUCdTdT GAUGUGUCAUUCCCUGCCAdTdT n.d. 783/784 TOP5253 GATGTGTCATTCCCTGCCAGAGT UCUGGCAGGGAAUGACACAdTdT UGUGUCAUUCCCUGCCAGAdTdT n.d. 785/786 TOP5254 CATTCCCTGCCAGAGTTTTGTCG ACAAAACUCUGGCAGGGAAdTdT UUCCCUGCCAGAGUUUUGUdTdT n.d. 787/788 TOP5255 CAGAGTTTTGTCGTCACTGACGT GUCAGUGACGACAAAACUCdTdT GAGUUUUGUCGUCACUGACdTdT n.d. 789/790 TOP5256 GAGTTTTGTCGTCACTGACGTTG ACGUCAGUGACGACAAAACdTdT GUUUUGUCGUCACUGACGUdTdT n.d. 791/792 TOP5257 TCACTGACGTTGACTACTT AAGUAGUCAACGUCAGUGAdtdt UCACUGACGUUGACTACUUdtdt n.d. 793/794 TOP5258 CACTGACGTTGACTACTTCTCAT GAGAAGUAGUCAACGUCAGdTdT CUGACGUUGACUACUUCUCdTdT n.d. 795/796 TOP5259 GACGTTGACTACTTCTCATTCCA GAAUGAGAAGUAGUCAACGdTdT CGUUGACUACUUCUCAUUCdTdT n.d. 797/798 TOP5260 GACTACTTCTCATTCCAACCAGA UGGUUGGAAUGAGAAGUAGdTdT CUACUUCUCAUUCCAACCAdTdT n.d. 799/800 TOP5261 TACTTCTCATTCCAACCAGACAG CUUCUCAUUCCAACCAGACdTdT CUUCUCAUUCCAACCAGACdTdT n.d. 801/802 TOP5262 CATTCCAACCAGACAGGCCTCTG GAGGCCUGUCUGGUUGGAAdTdT UUCCAACCAGACAGGCCUCdTdT n.d. 803/804 TOP5263 CAACCAGACAGGCCTCTGGGCAC GCCCAGAGGCCUGUCUGGUdTdT ACCAGACAGGCCUCUGGGCdTdT n.d. 805/806 TOP5264 AACCAGACAGGCCTCTGGGCACC CCAGACAGGCCUCUGGGCAdTdT CCAGACAGGCCUCUGGGCAdTdT n.d. 807/808 TOP5265 CACCCGGCTCACCGTCACTCTGA AGAGUGACGGUGAGCCGGGdTdT CCCGGCUCACCGUCACUCUdTdT n.d. 809/810 TOP5266 CACCGTCACTCTGACCCAGCATG UGCUGGGUCAGAGUGACGGdTdT CCGUCACUCUGACCCAGCAdTdT n.d. 811/812 TOP5267 CACTCTGACCCAGCATGTCCAGC UGGACAUGCUGGGUCAGAGdTdT CUCUGACCCAGCAUGUCCAdTdT n.d. 813/814 TOP5268 GACCCAGCATGTCCAGCCTCCTG GGAGGCUGGACAUGCUGGGdTdT CCCAGCAUGUCCAGCCUCCdTdT n.d. 815/816 TOP5269 CAGCATGTCCAGCCTCCTGAGCC CUCAGGAGGCUGGACAUGCdTdT GCAUGUCCAGCCUCCUGAGdTdT n.d. 817/818 TOP5270 CATGTCCAGCCTCCTGAGCCCAG GGGCUCAGGAGGCUGGACAdTdT UGUCCAGCCUCCUGAGCCCdTdT n.d. 819/820 TOP5271 GAGCCCAGGGACCTGCAGATCAG GAUCUGCAGGUCCCUGGGCdTdT GCCCAGGGACCUGCAGAUCdTdT n.d. 821/822 TOP5272 CAGGGACCTGCAGATCAGCACCG GUGCUGAUCUGCAGGUCCCdTdT GGGACCUGCAGAUCAGCACdTdT n.d. 823/824 TOP5273 GACCTGCAGATCAGCACCGACCA GUCGGUGCUGAUCUGCAGGdTdT CCUGCAGAUCAGCACCGACdTdT n.d. 825/826 TOP5274 CAGATCAGCACCGACCAGGACCA GUCCUGGUCGGUGCUGAUCdTdT GAUCAGCACCGACCAGGACdTdT n.d. 827/828 TOP5275 GATCAGCACCGACCAGGACCACT UGGUCCUGGUCGGUGCUGAdTdT UCAGCACCGACCAGGACCAdTdT n.d. 829/830 TOP5276 CAGCACCGACCAGGACCACTTCC AAGUGGUCCUGGUCGGUGCdTdT GCACCGACCAGGACCACUUdTdT n.d. 831/832 TOP5277 CACCGACCAGGACCACTTCCTGC AGGAAGUGGUCCUGGUCGGdTdT CCGACCAGGACCACUUCCUdTdT n.d. 833/834 TOP5278 GACCAGGACCACTTCCTGCTGAC CAGCAGGAAGUGGUCCUGGdTdT CCAGGACCACUUCCUGCUGdTdT n.d. 835/836 TOP5279 CAGGACCACTTCCTGCTGACCTG GGUCAGCAGGAAGUGGUCCdTdT GGACCACUUCCUGCUGACCdTdT n.d. 837/838 TOP5280 GACCACTTCCTGCTGACCTGGAG CCAGGUCAGCAGGAAGUGGdTdT CCACUUCCUGCUGACCUGGdTdT n.d. 839/840 TOP5281 CACTTCCTGCTGACCTGGAGTGT ACUCCAGGUCAGCAGGAAGdTdT CUUCCUGCUGACCUGGAGUdTdT n.d. 841/842 TOP5282 GACCTGGAGTGTGGCCCTTGGGA CCAAGGGCCACACUCCAGGdTdT CCUGGAGUGUGGCCCUUGGdTdT n.d. 843/844 TOP5283 GAGTGTGGCCCTTGGGAGTCCCC GGACUCCCAAGGGCCACACdTdT GUGUGGCCCUUGGGAGUCCdTdT n.d. 845/846 TOP5284 GAGTCCCCAGAGCCACTGGTTGT AACCAGUGGCUCUGGGGACdTdT GUCCCCAGAGCCACUGGUUdTdT n.d. 847/848 TOP5285 CAGAGCCACTGGTTGTCCCCAGG UGGGGACAACCAGUGGCUCdTdT GAGCCACUGGUUGUCCCCAdTdT n.d. 849/850 TOP5286 GCCACTGGTTGTCCCCAGG CCUGGGGACAACCAGUGGCdtdt GCCACUGGUUGUCCCCAGGdtdt n.d. 851/852 TOP5287 GATCTGGAGTTTGAGGTGGTCTA GACCACCUCAAACUCCAGAdTdT UCUGGAGUUUGAGGUGGUCdTdT n.d. 853/854 TOP5288 TGGAGTTTGAGGTGGTCTA UAGACCACCUCAAACUCCAdtdt UGGAGUUUGAGGUGGUCUAdtdt n.d. 855/856 TOP5289 GAGTTTGAGGTGGTCTACAAGCG CUUGUAGACCACCUCAAACdTdT GUUUGAGGUGGUCUACAAGdTdT n.d. 857/858 TOP5290 GAGGTGGTCTACAAGCGGCTTCA AAGCCGCUUGUAGACCACCdTdT GGUGGUCUACAAGCGGCUUdTdT n.d. 859/860 TOP5291 TACAAGCGGCTTCAGGACTCTTG AGAGUCCUGAAGCCGCUUGdTdT CAAGCGGCUUCAGGACUCUdTdT n.d.

861/862 TOP5292 CAAGCGGCTTCAGGACTCTTGGG CAAGAGUCCUGAAGCCGCUdTdT AGCGGCUUCAGGACUCUUGdTdT n.d. 863/864 TOP5293 AAGCGGCTTCAGGACTCTTGGGA CCAAGAGUCCUGAAGCCGCdTdT GCGGCUUCAGGACUCUUGGdTdT n.d. 865/866 TOP5294 CAGGACTCTTGGGAGGACGCAGC UGCGUCCUCCCAAGAGUCCdTdT GGACUCUUGGGAGGACGCAdTdT n.d. 867/868 TOP5295 GACTCTTGGGAGGACGCAGCCAT GGCUGCGUCCUCCCAAGAGdTdT CUCUUGGGAGGACGCAGCCdTdT n.d. 869/870 TOP5296 GAGGACGCAGCCATCCTCCTCTC GAGGAGGAUGGCUGCGUCCdTdT GGACGCAGCCAUCCUCCUCdTdT n.d. 871/872 TOP5297 GACGCAGCCATCCTCCTCTCCAA GGAGAGGAGGAUGGCUGCGdTdT CGCAGCCAUCCUCCUCUCCdTdT n.d. 873/874 TOP5298 CAGCCATCCTCCTCTCCAACACC UGUUGGAGAGGAGGAUGGCdTdT GCCAUCCUCCUCUCCAACAdTdT n.d. 875/876 TOP5299 CATCCTCCTCTCCAACACCTCCC GAGGUGUUGGAGAGGAGGAdTdT UCCUCCUCUCCAACACCUCdTdT n.d. 877/878 TOP5300 CAACACCTCCCAGGCCACCCTGG AGGGUGGCCUGGGAGGUGUdTdT ACACCUCCCAGGCCACCCUdTdT n.d. 879/880 TOP5301 AACACCTCCCAGGCCACCCTGGG CAGGGUGGCCUGGGAGGUGdTdT CACCUCCCAGGCCACCCUGdTdT n.d. 881/882 TOP5302 CAGAGCACCTCATGCCCAGCAGC UGCUGGGCAUGAGGUGCUCdTdT GAGCACCUCAUGCCCAGCAdTdT n.d. 883/884 TOP5303 GAGCACCTCATGCCCAGCAGCAC GCUGCUGGGCAUGAGGUGCdTdT GCACCUCAUGCCCAGCAGCdTdT n.d. 885/886 TOP5304 CACCTCATGCCCAGCAGCACCTA GGUGCUGCUGGGCAUGAGGdTdT CCUCAUGCCCAGCAGCACCdTdT n.d. 887/888 TOP5305 CATGCCCAGCAGCACCTACGTGG ACGUAGGUGCUGCUGGGCAdTdT UGCCCAGCAGCACCUACGUdTdT n.d. 889/890 TOP5306 CAGCACCTACGTGGCCCGAGTAC ACUCGGGCCACGUAGGUGCdTdT GCACCUACGUGGCCCGAGUdTdT n.d. 891/892 TOP5307 GCACCTACGTGGCCCGAGT ACUCGGGCCACGUAGGUGCdtdt GCACCUACGUGGCCCGAGUdtdt n.d. 893/894 TOP5308 CACCTACGTGGCCCGAGTACGGA CGUACUCGGGCCACGUAGGdTdT CCUACGUGGCCCGAGUACGdTdT n.d. 895/896 TOP5309 CAGGTTCTCGGCTCTCAGGACGT GUCCUGAGAGCCGAGAACCdTdT GGUUCUCGGCUCUCAGGACdTdT n.d. 897/898 TOP5310 CAGGACGTCCCAGCAAGTGGAGC UCCACUUGCUGGGACGUCCdTdT GGACGUCCCAGCAAGUGGAdTdT n.d. 899/900 TOP5311 GACGTCCCAGCAAGTGGAGCCCA GGCUCCACUUGCUGGGACGdTdT CGUCCCAGCAAGUGGAGCCdTdT n.d. 901/902 TOP5312 CAGCAAGTGGAGCCCAGAGGTTT ACCUCUGGGCUCCACUUGCdTdT GCAAGUGGAGCCCAGAGGUdTdT n.d. 903/904 TOP5313 CAAGTGGAGCCCAGAGGTTTGCT CAAACCUCUGGGCUCCACUdTdT AGUGGAGCCCAGAGGUUUGdTdT n.d. 905/906 TOP5314 CAAGTGGAGCCCAGAGGTT AACCUCUGGGCUCCACUUGdtdt CAAGUGGAGCCCAGAGGUUdtdt n.d. 907/908 TOP5315 AAGTGGAGCCCAGAGGTTTGCTG GCAAACCUCUGGGCUCCACdTdT GUGGAGCCCAGAGGUUUGCdTdT n.d. 909/910 TOP5316 GAGCCCAGAGGTTTGCTGGGACT UCCCAGCAAACCUCUGGGCdTdT GCCCAGAGGUUUGCUGGGAdTdT n.d. 911/912 TOP5317 CAGAGGTTTGCTGGGACTCCCAG GGGAGUCCCAGCAAACCUCdTdT GAGGUUUGCUGGGACUCCCdTdT n.d. 913/914 TOP5318 GAGGTTTGCTGGGACTCCCAGCC CUGGGAGUCCCAGCAAACCdTdT GGUUUGCUGGGACUCCCAGdTdT n.d. 915/916 TOP5319 GATGAGGCCCAGCCCCAGAACCT GUUCUGGGGCUGGGCCUCAdTdT UGAGGCCCAGCCCCAGAACdTdT n.d. 917/918 TOP5320 CAGCCCCAGAACCTGGAGTGCTT GCACUCCAGGUUCUGGGGCdTdT GCCCCAGAACCUGGAGUGCdTdT n.d. 919/920 TOP5321 CAGAACCTGGAGTGCTTCTTTGA AAAGAAGCACUCCAGGUUCdTdT GAACCUGGAGUGCUUCUUUdTdT n.d. 921/922 TOP5322 GAACCTGGAGTGCTTCTTTGACG UCAAAGAAGCACUCCAGGUdTdT ACCUGGAGUGCUUCUUUGAdTdT n.d. 923/924 TOP5323 AACCTGGAGTGCTTCTTTGACGG GUCAAAGAAGCACUCCAGGdTdT CCUGGAGUGCUUCUUUGACdTdT n.d. 925/926 TOP5324 CAGCTGCTCCTGGGAGGTGAGGA CUCACCUCCCAGGAGCAGCdTdT GCUGCUCCUGGGAGGUGAGdTdT n.d. 927/928 TOP5325 GAGGTGAGGAAGGAGGTGGCCAG GGCCACCUCCUUCCUCACCdTdT GGUGAGGAAGGAGGUGGCCdTdT n.d. 929/930 TOP5326 GAGGAAGGAGGTGGCCAGCTCGG GAGCUGGCCACCUCCUUCCdTdT GGAAGGAGGUGGCCAGCUCdTdT n.d. 931/932 TOP5327 GAAGGAGGTGGCCAGCTCGGTCT ACCGAGCUGGCCACCUCCUdTdT AGGAGGUGGCCAGCUCGGUdTdT n.d. 933/934 TOP5328 AAGGAGGTGGCCAGCTCGGTCTC GACCGAGCUGGCCACCUCCdTdT GGAGGUGGCCAGCUCGGUCdTdT n.d. 935/936 TOP5329 GAGGTGGCCAGCTCGGTCTCCTT GGAGACCGAGCUGGCCACCdTdT GGUGGCCAGCUCGGUCUCCdTdT n.d. 937/938 TOP5330 CAGCTCGGTCTCCTTTGGCCTAT AGGCCAAAGGAGACCGAGCdTdT GCUCGGUCUCCUUUGGCCUdTdT n.d. 939/940 TOP5330 TATTCTACAAGCCCAGCCCAGAT CUGGGCUGGGCUUGUAGAAdTdT UUCUACAAGCCCAGCCCAGdTdT n.d. 941/942 TOP5332 TACAAGCCCAGCCCAGATGCAGG UGCAUCUGGGCUGGGCUUGdTdT CAAGCCCAGCCCAGAUGCAdTdT n.d. 943/944 TOP5333 GAGGAAGAGTGCTCCCCAGTGCT CACUGGGGAGCACUCUUCCdTdT GGAAGAGUGCUCCCCAGUGdTdT n.d. 945/946 TOP5334 GAAGAGTGCTCCCCAGTGCTGAG CAGCACUGGGGAGCACUCUdTdT AGAGUGCUCCCCAGUGCUGdTdT n.d. 947/948 TOP5335 AAGAGTGCTCCCCAGTGCTGAGG UCAGCACUGGGGAGCACUCdTdT GAGUGCUCCCCAGUGCUGAdTdT n.d. 949/950 TOP5336 GAGTGCTCCCCAGTGCTGAGGGA CCUCAGCACUGGGGAGCACdTdT GUGCUCCCCAGUGCUGAGGdTdT n.d. 951/952 TOP5337 CAGCCTCCACACCAGGCACCACT UGGUGCCUGGUGUGGAGGCdTdT GCCUCCACACCAGGCACCAdTdT n.d. 953/954 TOP5338 CACACCAGGCACCACTGCCAGAT CUGGCAGUGGUGCCUGGUGdTdT CACCAGGCACCACUGCCAGdTdT n.d. 955/956 TOP5339 CACCAGGCACCACTGCCAGATTC AUCUGGCAGUGGUGCCUGGdTdT CCAGGCACCACUGCCAGAUdTdT n.d. 957/958 TOP5340 CAGGCACCACTGCCAGATTCCCG GGAAUCUGGCAGUGGUGCCdTdT GGCACCACUGCCAGAUUCCdTdT n.d. 959/960 TOP5341 CACCACTGCCAGATTCCCGTGCC CACGGGAAUCUGGCAGUGGdTdT CCACUGCCAGAUUCCCGUGdTdT n.d. 961/962 TOP5342 CACTGCCAGATTCCCGTGCCCGA GGGCACGGGAAUCUGGCAGdTdT CUGCCAGAUUCCCGUGCCCdTdT n.d. 963/964 TOP5343 GACCCACGGCCAATACATCGTCT ACGAUGUAUUGGCCGUGGGdTdT CCCACGGCCAAUACAUCGUdTdT n.d. 965/966 TOP5344 CACGGCCAATACATCGTCTCTGT AGAGACGAUGUAUUGGCCGdTdT CGGCCAAUACAUCGUCUCUdTdT n.d. 967/968 TOP5345 CAATACATCGTCTCTGTTCAGCC CUGAACAGAGACGAUGUAUdTdT AUACAUCGUCUCUGUUCAGdTdT n.d. 969/970 TOP5346 AATACATCGTCTCTGTTCAGCCA GCUGAACAGAGACGAUGUAdTdT UACAUCGUCUCUGUUCAGCdTdT n.d. 971/972 TOP5347 TACATCGTCTCTGTTCAGCCAAG UGGCUGAACAGAGACGAUGdTdT CAUCGUCUCUGUUCAGCCAdTdT n.d. 973/974 TOP5348 CATCGTCTCTGTTCAGCCAAGGA CUUGGCUGAACAGAGACGAdTdT UCGUCUCUGUUCAGCCAAGdTdT n.d. 975/976 TOP5101 CAGCCAAGGAGGGCAGAGAAACA UUUCUCUGCCCUCCUUGGCdTdT GCCAAGGAGGGCAGAGAAAdTdT <20% 977/978 TOP5114 CAGCCAAGGAGGGCAGAGA UCUCUGCCCUCCUUGGCUGdtdt CAGCCAAGGAGGGCAGAGAdtdt <20% 979/980 TOP5349 CAAGGAGGGCAGAGAAACACATA UGUGUUUCUCUGCCCUCCUdTdT AGGAGGGCAGAGAAACACAdTdT n.d. 981/982 TOP5350 CAAGGAGGGCAGAGAAACA UGUUUCUCUGCCCUCCUUGdtdt CAAGGAGGGCAGAGAAACAdtdt n.d. 983/984 TOP5351 AAGGAGGGCAGAGAAACACATAA AUGUGUUUCUCUGCCCUCCdTdT GGAGGGCAGAGAAACACAUdTdT n.d. 985/986 TOP5100 GAGGGCAGAGAAACACATAAAGA UUUAUGUGUUUCUCUGCCCdTdT GGGCAGAGAAACACAUAAAdTdT >40% 987/988 TOP5102 GCAGAGAAACACATAAAGA UCUUUAUGUGUUUCUCUGCdtdt GCAGAGAAACACAUAAAGAdtdt >40% 989/990 TOP5352 CAGAGAAACACATAAAGAGCTCA AGCUCUUUAUGUGUUUCUCdTdT GAGAAACACAUAAAGAGCUdTdT n.d. 991/992 TOP5353 GAGAAACACATAAAGAGCTCAGT UGAGCUCUUUAUGUGUUUCdTdT GAAACACAUAAAGAGCUCAdTdT n.d. 993/994 TOP5109 AGAAACACATAAAGAGCTC GAGCUCUUUAUGUGUUUCUdtdt AGAAACACAUAAAGAGCUCdtdt <20% 995/996 TOP5354 GAAACACATAAAGAGCTCAGTGA ACUGAGCUCUUUAUGUGUUdTdT AACACAUAAAGAGCUCAGUdTdT n.d. 997/996 TOP5355 AAACACATAAAGAGCTCAGTGAA CACUGAGCUCUUUAUGUGUdTdT ACACAUAAAGAGCUCAGUGdTdT n.d. 999/1000 TOP5115 AACACATAAAGAGCTCAGTGAAC UCACUGAGCUCUUUAUGUCdTdT CACAUAAAGAGCUCAGUGAdTdT >40% 1001/1002 TOP5104 CACATAAAGAGCTCAGTGAACAT GUUCACUGAGCUCUUUAUGdTdT CAUAAAGAGCUCAGUGAACdTdT >40% 1003/1004 TOP5106 ACATAAAGAGCTCAGTGAA UUCACUGAGCUCUUUAUGUdtdt ACAUAAAGAGCUCAGUGAAdtdt 20-40% 1005/1006 TOP5110 CATAAAGAGCTCAGTGAACATCC AUGUUCACUGAGCUCUUUAdTdT UAAAGAGCUCAGUGAACAUdTdT 20-40% 1007/1008 TOP5108 ATAAAGAGCTCAGTGAACA UGUUCACUGAGCUCUUUAUdtdt CGCAGAAAGUGGGAGGAGAdtdt 20-40% 1009/1010 TOP5356 TAAAGAGCTCAGTGAACATCCAG GGAUGUUCACUGAGCUCUUdTdT AAGAGCUCAGUGAACAUCCdTdT n.d. 1011/1012 TOP5357 AAAGAGCTCAGTGAACATCCAGA UGGAUGUUCACUGAGCUCUdTdT AGAGCUCAGUGAACAUCCAdTdT n.d. 1013/1014 TOP5358 AAGAGCTCAGTGAACATCCAGAT CUGGAUGUUCACUGAGCUCdTdT GAGCUCAGUGAACAUCCAGdTdT n.d. 1015/1016 TOP5359 GAGCTCAGTGAACATCCAGATGG AUCUGGAUGUUCACUGAGCdTdT GCUCAGUGAACAUCCAGAUdTdT n.d. 1017/1018 TOP5360 CAGTGAACATCCAGATGGCCCCT GGGCCAUCUGGAUGUUCACdTdT GUGAACAUCCAGAUGGCCCdTdT n.d. 1019/1020 TOP5361 GAACATCCAGATGGCCCCTCCAT GGAGGGGCCAUCUGGAUGUdTdT ACAUCCAGAUGGCCCCUCCdTdT n.d. 1021/1022 TOP5362 AACATCCAGATGGCCCCTCCATC UGGAGGGGCCAUCUGGAUGdTdT CAUCCAGAUGGCCCCUCCAdTdT n.d. 1023/1024 TOP5363 CATCCAGATGGCCCCTCCATCCC GAUGGAGGGGCCAUCUGGAdTdT UCCAGAUGGCCCCUCCAUCdTdT n.d. 1025/1026 TOP5364 CAGATGGCCCCTCCATCCCTCAA GAGGGAUGGAGGGGCCAUCdTdT GAUGGCCCCUCCAUCCCUCdTdT n.d. 1027/1028 TOP5365 GATGGCCCCTCCATCCCTCAACG UUGAGGGAUGGAGGGGCCAdTdT

UGGCCCCUCCAUCCCUCAAdTdT n.d. 1029/1030 TOP5366 CATCCCTCAACGTGACCAAGGAT CCUUGGUCACGUUGAGGGAdTdT UCCCUCAACGUGACCAAGGdTdT n.d. 1031/1032 TOP5367 CAACGTGACCAAGGATGGAGACA UCUCCAUCCUUGGUCACGUdTdT ACGUGACCAAGGAUGGAGAdTdT n.d. 1033/1034 TOP5368 AACGTGACCAAGGATGGAGACAG GUCUCCAUCCUUGGUCACGdTdT CGUGACCAAGGAUGGAGACdTdT n.d. 1035/1036 TOP5369 GACCAAGGATGGAGACAGCTACA UAGCUGUCUCCAUCCUUGGdTdT CCAAGGAUGGAGACAGCUAdTdT n.d. 1037/1038 TOP5370 CAAGGATGGAGACAGCTACAGCC CUGUAGCUGUCUCCAUCCUdTdT AGGAUGGAGACAGCUACAGdTdT n.d. 1039/1040 TOP5371 AAGGATGGAGACAGCTACAGCCT GCUGUAGCUGUCUCCAUCCdTdT GGAUGGAGACAGCUACAGCdTdT n.d. 1041/1042 TOP5372 GATGGAGACAGCTACAGCCTGCG CAGGCUGUAGCUGUCUCCAdTdT UGGAGACAGCUACAGCCUGdTdT n.d. 1043/1044 TOP5373 GAGACAGCTACAGCCTGCGCTGG AGCGCAGGCUGUAGCUGUCdTdT GACAGCUACAGCCUGCGCUdTdT n.d. 1045/1046 TOP5374 GACAGCTACAGCCTGCGCTGGGA CCAGCGCAGGCUGUAGCUGdTdT CAGCUACAGCCUGCGCUGGdTdT n.d. 1047/1048 TOP5375 CAGCTACAGCCTGCGCTGGGAAA UCCCAGCGCAGGCUGUAGCdTdT GCUACAGCCUGCGCUGGGAdTdT n.d. 1049/1050 TOP5376 TACAGCCTGCGCTGGGAAACAAT UGUUUCCCAGCGCAGGCUGdTdT CAGCCUGCGCUGGGAAACAdTdT n.d. 1051/1052 TOP5377 CAGCCTGCGCTGGGAAACAATGA AUUGUUUCCCAGCGCAGGCdTdT GCCUGCGCUGGGAAACAAUdTdT n.d. 1053/1054 TOP5105 GCGCTGGGAAACAATGAAA UUUCAUUGUUUCCCAGCGCdtdt GCGCUGGGAAACAAUGAAAdtdt 20-40% 1055/1056 TOP5112 GCTGGGAAACAATGAAAAT AUUUUCAUUGUUUCCCAGCdtdt GCUGGGAAACAAUGAAAAUdtdt 20-40% 1057/1058 TOP5378 AAACAATGAAAATGCGATACGAA CGUAUCGCAUUUUCAUUGUdTdT ACAAUGAAAAUGCGAUACGdTdT n.d. 1059/1060 TOP5379 AACAATGAAAATGCGATACGAAC UCGUAUCGCAUUUUCAUUGdTdT CAAUGAAAAUGCGAUACGAdTdT n.d. 1061/1062 TOP5380 CAATGAAAATGCGATACGAACAC GUUCGUAUCGCAUUUUCAUdTdT AUGAAAAUGCGAUACGAACdTdT n.d. 1063/1064 TOP5116 AATGAAAATGCGATACGAACACA UGUUCGUAUCGCAUUUUCAdTdT UGAAAAUGCGAUACGAACAdTdT <20% 1065/1066 TOP5381 GAAAATGCGATACGAACACATAG AUGUGUUCGUAUCGCAUUUdTdT AAAUGCGAUACGAACACAUdTdT n.d. 1067/1068 TOP5382 AAAATGCGATACGAACACATAGA UAUGUGUUCGUAUCGCAUUdTdT AAUGCGAUACGAACACAUAdTdT n.d. 1069/1070 TOP5383 AAATGCGATACGAACACATAGAC CUAUGUGUUCGUAUCGCAUdTdT AUGCGAUACGAACACAUAGdTdT n.d. 1071/1072 TOP5384 AATGCGATACGAACACATAGACC UCUAUGUGUUCGUAUCGCAdTdT UGCGAUACGAACACAUAGAdTdT n.d. 1073/1074 TOP5385 CACATAGACCACACATTTGAGAT CUCAAAUGUGUGGUCUAUGdTdT CAUAGACCACACAUUUGAGdTdT n.d. 1075/1076 TOP5386 GATACGAACACATAGACCACACA UGUGGUCUAUGUGUUCGUAdTdT UACGAACACAUAGACCACAdTdT n.d. 1077/1078 TOP5117 GATACGAACACATAGACCA UGGUCUAUGUGUUCGUAUCdtdt GAUACGAACACAUAGACCAdtdt >40% 1079/1080 TOP5387 TACGAACACATAGACCACACATT UGUGUGGUCUAUGUGUUCGdTdT CGAACACAUAGACCACACAdTdT n.d. 1081/1082 TOP5107 GAACACATAGACCACACATTTGA AAAUGUGUGGUCUAUGUGUdTdT ACACAUAGACCACACAUUUdTdT >40% 1083/1084 TOP5388 AACACATAGACCACACATTTGAG CAAAUGUGUGGUCUAUGUGdTdT CACAUAGACCACACAUUUGdTdT n.d. 1085/1086 TOP5389 CATAGACCACACATTTGAGATCC AUCUCAAAUGUGUGGUCUAdTdT UAGACCACACAUUUGAGAUdTdT n.d. 1087/1088 TOP5390 TAGACCACACATTTGAGATCCAG GGAUCUCAAAUGUGUGGUCdTdT GACCACACAUUUGAGAUCCdTdT n.d. 1089/1090 TOP5391 GACCACACATTTGAGATCCAGTA CUGGAUCUCAAAUGUGUGGdTdT CCACACAUUUGAGAUCCAGdTdT n.d. 1091/1092 TOP5392 CACACATTTGAGATCCAGTACAG GUACUGGAUCUCAAAUGUGdTdT CACAUUUGAGAUCCAGUACdTdT n.d. 1093/1094 TOP5393 CACATTTGAGATCCAGTACAGGA CUGUACUGGAUCUCAAAUGdTdT CAUUUGAGAUCCAGUACAGdTdT n.d. 1095/1096 TOP5394 CATTTGAGATCCAGTACAGGAAA UCCUGUACUGGAUCUCAAAdTdT UUUGAGAUCCAGUACAGGAdTdT n.d. 1097/1098 TOP5395 GAGATCCAGTACAGGAAAGACAC GUCUUUCCUGUACUGGAUCdTdT GAUCCAGUACAGGAAAGACdTdT n.d. 1099/1100 TOP5396 GATCCAGTACAGGAAAGACACGG GUGUCUUUCCUGUACUGGAdTdT UCCAGUACAGGAAAGACACdTdT n.d. 1101/1102 TOP5397 CAGTACAGGAAAGACACGGCCAC GGCCGUGUCUUUCCUGUACdTdT GUACAGGAAAGACACGGCCdTdT n.d. 1103/1104 TOP5398 TACAGGAAAGACACGGCCACGTG CGUGGCCGUGUCUUUCCUGdTdT CAGGAAAGACACGGCCACGdTdT n.d. 1105/1106 TOP5399 CAGGAAAGACACGGCCACGTGGA CACGUGGCCGUGUCUUUCCdTdT GGAAAGACACGGCCACGUGdTdT n.d. 1107/1108 TOP5400 GAAAGACACGGCCACGTGGAAGG UUCCACGUGGCCGUGUCUUdTdT AAGACACGGCCACGUGGAAdTdT n.d. 1109/1110 TOP5401 AAAGACACGGCCACGTGGAAGGA CUUCCACGUGGCCGUGUCUdTdT AGACACGGCCACGUGGAAGdTdT n.d. 1111/1112 TOP5402 AAGACACGGCCACGTGGAAGGAC CCUUCCACGUGGCCGUGUCdTdT GACACGGCCACGUGGAAGGdTdT n.d. 1113/1114 TOP5403 GACACGGCCACGTGGAAGGACAG GUCCUUCCACGUGGCCGUGdTdT CACGGCCACGUGGAAGGACdTdT n.d. 1115/1116 TOP5404 CACGGCCACGTGGAAGGACAGCA CUGUCCUUCCACGUGGCCGdTdT CGGCCACGUGGAAGGACAGdTdT n.d. 1117/1118 TOP5103 CCACGTGGAAGGACAGCAA UUGCUGUCCUUCCACGUGGdtdt CCACGUGGAAGGACAGCAAdtdt 20-40% 1119/1120 TOP5405 CACGTGGAAGGACAGCAAGACCG GUCUUGCUGUCCUUCCACGdTdT CGUGGAAGGACAGCAAGACdTdT n.d. 1121/1122 TOP5113 ACGTGGAAGGACAGCAAGA UCUUGCUGUCCUUCCACGUdtdt ACGUGGAAGGACAGCAAGAdtdt 20-40% 1123/1124 TOP5111 GGAAGGACAGCAAGACCGA UCGGUCUUGCUGUCCUUCCdtdt GGAAGGACAGCAAGACCGAdtdt 20-40% 1125/1126 TOP5406 GAAGGACAGCAAGACCGAGACCC GUCUCGGUCUUGCUGUCCUdTdT AGGACAGCAAGACCGAGACdTdT n.d. 1127/1128 TOP5407 AAGGACAGCAAGACCGAGACCCT GGUCUCGGUCUUGCUGUCCdTdT GGACAGCAAGACCGAGACCdTdT n.d. 1129/1130 TOP5118 CAGGAGGGTGGGAGCCAGA UCUGGCUCCCACCCUCCUGdtdt CAGGAGGGUGGGAGCCAGAdtdt <20% 1131/1132 TOP5408 GACAGCAAGACCGAGACCCTCCA GAGGGUCUCGGUCUUGCUGdTdT CAGCAAGACCGAGACCCUCdTdT n.d. 1133/1134 TOP5409 CAGCAAGACCGAGACCCTCCAGA UGGAGGGUCUCGGUCUUGCdTdT GCAAGACCGAGACCCUCCAdTdT n.d. 1135/1136 TOP5410 CAAGACCGAGACCCTCCAGAACG UUCUGGAGGGUCUCGGUCUdTdT AGACCGAGACCCUCCAGAAdTdT n.d. 1137/1138 TOP5411 AAGACCGAGACCCTCCAGAACGC GUUCUGGAGGGUCUCGGUCdTdT GACCGAGACCCUCCAGAACdTdT n.d. 1139/1140 TOP5412 GACCGAGACCCTCCAGAACGCCC GCGUUCUGGAGGGUCUCGGdTdT CCGAGACCCUCCAGAACGCdTdT n.d. 1141/1142 TOP5413 GAGACCCTCCAGAACGCCCACAG GUGGGCGUUCUGGAGGGUCdTdT GACCCUCCAGAACGCCCACdTdT n.d. 1143/1144 TOP5414 GACCCTCCAGAACGCCCACAGCA CUGUGGGCGUUCUGGAGGGdTdT CCCUCCAGAACGCCCACAGdTdT n.d. 1145/1146 TOP5415 CAGAACGCCCACAGCATGGCCCT GGCCAUGCUGUGGGCGUUCdTdT GAACGCCCACAGCAUGGCCdTdT n.d. 1147/1148 TOP5416 GAACGCCCACAGCATGGCCCTGC AGGGCCAUGCUGUGGGCGUdTdT ACGCCCACAGCAUGGCCCUdTdT n.d. 1149/1150 TOP5417 AACGCCCACAGCATGGCCCTGCC CAGGGCCAUGCUGUGGGCGdTdT CGCCCACAGCAUGGCCCUGdTdT n.d. 1151/1152 TOP5418 CGCCCACAGCATGGCCCTG CAGGGCCAUGCUGUGGGCGdtdt CGCCCACAGCAUGGCCCUGdtdt n.d. 1153/1154 TOP5419 GAGCCCTCCACCAGGTACTGGGC CCAGUACCUGGUGGAGGGCdTdT GCCCUCCACCAGGUACUGGdTdT n.d. 1155/1156 TOP5420 CACCAGGTACTGGGCCAGGGTGA ACCCUGGCCCAGUACCUGGdTdT CCAGGUACUGGGCCAGGGUdTdT n.d. 1157/1158 TOP5421 CAGGTACTGGGCCAGGGTGAGGG CUCACCCUGGCCCAGUACCdTdT GGUACUGGGCCAGGGUGAGdTdT n.d. 1159/1160 TOP5422 CAGGGTGAGGGTCAGGACCTCCC GAGGUCCUGACCCUCACCCdTdT GGGUGAGGGUCAGGACCUCdTdT n.d. 1161/1162 TOP5423 GACCTCCCGCACCGGCTACAACG UUGUAGCCGGUGCGGGAGGdTdT CCUCCCGCACCGGCUACAAdTdT n.d. 1163/1164 TOP5424 CACCGGCTACAACGGGATCTGGA CAGAUCCCGUUGUAGCCGGdTdT CCGGCUACAACGGGAUCUGdTdT n.d. 1165/1166 TOP5425 TACAACGGGATCTGGAGCGAGTG CUCGCUCCAGAUCCCGUUGdTdT CAACGGGAUCUGGAGCGAGdTdT n.d. 1167/1168 TOP5426 CAACGGGATCTGGAGCGAGTGGA CACUCGCUCCAGAUCCCGUdTdT ACGGGAUCUGGAGCGAGUGdTdT n.d. 1169/1170 TOP5427 AACGGGATCTGGAGCGAGTGGAG CCACUCGCUCCAGAUCCCGdTdT CGGGAUCUGGAGCGAGUGGdTdT n.d. 1171/1172 TOP5428 GATCTGGAGCGAGTGGAGTGAGG UCACUCCACUCGCUCCAGAdTdT UCUGGAGCGAGUGGAGUGAdTdT n.d. 1173/1174 TOP5429 GACACCGAGTCGGTGCTGCCTAT AGGCAGCACCGACUCGGUGdTdT CACCGAGUCGGUGCUGCCUdTdT n.d. 1175/1176 TOP5430 CACCGAGTCGGTGCTGCCTATGT AUAGGCAGCACCGACUCGGdTdT CCGAGUCGGUGCUGCCUAUdTdT n.d. 1177/1178 TOP5431 GAGTCGGTGCTGCCTATGTGGGT CCACAUAGGCAGCACCGACdTdT GUCGGUGCUGCCUAUGUGGdTdT n.d. 1179/1180 TOP5432 TATGTGGGTGCTGGCCCTCATCG AUGAGGGCCAGCACCCACAdTdT UGUGGGUGCUGGCCCUCAUdTdT n.d. 1181/1182 TOP5433 CATCGTGATCTTCCTCACCATCG AUGGUGAGGAAGAUCACGAdTdT UCGUGAUCUUCCUCACCAUdTdT n.d. 1183/1184 TOP5434 GATCTTCCTCACCATCGCTGTGC ACAGCGAUGGUGAGGAAGAdTdT UCUUCCUCACCAUCGCUGUdTdT n.d. 1185/1186 TOP5435 CACCATCGCTGTGCTCCTGGCCC GCCAGGAGCACAGCGAUGGdTdT CCAUCGCUGUGCUCCUGGCdTdT n.d. 1187/1188 TOP5436 CATCGCTGTGCTCCTGGCCCTCC AGGGCCAGGAGCACAGCGAdTdT UCGCUGUGCUCCUGGCCCUdTdT n.d. 1189/1190 TOP5437 CATCTACGGGTACAGGCTGCGCA CGCAGCCUGUACCCGUAGAdTdT UCUACGGGUACAGGCUGCGdTdT n.d. 1191/1192 TOP5438 TACGGGTACAGGCTGCGCAGAAA UCUGCGCAGCCUGUACCCGdTdT CGGGUACAGGCUGCGCAGAdTdT n.d. 1193/1194 TOP5439 GGGTACAGGCTGCGCAGAA UUCUGCGCAGCCUGUACCCdtdt GGGUACAGGCUGCGCAGAAdtdt n.d.

1195/1196 TOP5440 GGTACAGGCTGCGCAGAAA UUUCUGCGCAGCCUGUACCdtdt GGUACAGGCUGCGCAGAAAdtdt n.d. 1197/1198 TOP5441 TACAGGCTGCGCAGAAAGTGGGA CCACUUUCUGCGCAGCCUGdTdT CAGGCUGCGCAGAAAGUGGdTdT n.d. 1199/1200 TOP5442 CAGGCTGCGCAGAAAGTGGGAGG UCCCACUUUCUGCGCAGCCdTdT GGCUGCGCAGAAAGUGGGAdTdT n.d. 1201/1202 TOP5443 CGCAGAAAGTGGGAGGAGA UCUCCUCCCACUUUCUGCGdtdt CGCAGAAAGUGGGAGGAGAdtdt n.d. 1203/1204 TOP5444 GCAGAAAGTGGGAGGAGAA UUCUCCUCCCACUUUCUGCdtdt GCAGAAAGUGGGAGGAGAAdtdt n.d. 1205/1206 TOP5445 CAGAAAGTGGGAGGAGAAGATCC AUCUUCUCCUCCCACUUUCdTdT GAAAGUGGGAGGAGAAGAUdTdT n.d. 1207/1208 TOP5446 GAAAGTGGGAGGAGAAGATCCCC GGAUCUUCUCCUCCCACUUdTdT AAGUGGGAGGAGAAGAUCCdTdT n.d. 1209/1210 TOP5447 AAAGTGGGAGGAGAAGATCCCCA GGGAUCUUCUCCUCCCACUdTdT AGUGGGAGGAGAAGAUCCCdTdT n.d. 1211/1212 TOP5448 AAGTGGGAGGAGAAGATCCCCAA GGGGAUCUUCUCCUCCCACdTdT GUGGGAGGAGAAGAUCCCCdTdT n.d. 1213/1214 TOP5449 GAGGAGAAGATCCCCAACCCCAG GGGGUUGGGGAUCUUCUCCdTdT GGAGAAGAUCCCCAACCCCdTdT n.d. 1215/1216 TOP5450 GAGAAGATCCCCAACCCCAGCAA GCUGGGGUUGGGGAUCUUCdTdT GAAGAUCCCCAACCCCAGCdTdT n.d. 1217/1218 TOP5451 GAAGATCCCCAACCCCAGCAAGA UUGCUGGGGUUGGGGAUCUdTdT AGAUCCCCAACCCCAGCAAdTdT n.d. 1219/1220 TOP5452 AAGATCCCCAACCCCAGCAAGAG CUUGCUGGGGUUGGGGAUCdTdT GAUCCCCAACCCCAGCAAGdTdT n.d. 1221/1222 TOP5453 GATCCCCAACCCCAGCAAGAGCC CUCUUGCUGGGGUUGGGGAdTdT UCCCCAACCCCAGCAAGAGdTdT n.d. 1223/1224 TOP5454 CAACCCCAGCAAGAGCCACCTGT AGGUGGCUCUUGCUGGGGUdTdT ACCCCAGCAAGAGCCACCUdTdT n.d. 1225/1226 TOP5455 AACCCCAGCAAGAGCCACCTGTT CAGGUGGCUCUUGCUGGGGdTdT CCCCAGCAAGAGCCACCUGdTdT n.d. 1227/1228 TOP5456 CAGCAAGAGCCACCTGTTCCAGA UGGAACAGGUGGCUCUUGCdTdT GCAAGAGCCACCUGUUCCAdTdT n.d. 1229/1230 TOP5457 CAAGAGCCACCTGTTCCAGAACG UUCUGGAACAGGUGGCUCUdTdT AGAGCCACCUGUUCCAGAAdTdT n.d. 1231/1232 TOP5458 AAGAGCCACCTGTTCCAGAACGG GUUCUGGAACAGGUGGCUCdTdT GAGCCACCUGUUCCAGAACdTdT n.d. 1233/1234 TOP5459 GAGCCACCTGTTCCAGAACGGGA CCGUUCUGGAACAGGUGGCdTdT GCCACCUGUUCCAGAACGGdTdT n.d. 1235/1236 TOP5460 CACCTGTTCCAGAACGGGAGCGC GCUCCCGUUCUGGAACAGGdTdT CCUGUUCCAGAACGGGAGCdTdT n.d. 1237/1238 TOP5461 CAGAACGGGAGCGCAGAGCTTTG AAGCUCUGCGCUCCCGUUCdTdT GAACGGGAGCGCAGAGCUUdTdT n.d. 1239/1240 TOP5462 GAACGGGAGCGCAGAGCTTTGGC CAAAGCUCUGCGCUCCCGUdTdT ACGGGAGCGCAGAGCUUUGdTdT n.d. 1241/1242 TOP5463 AACGGGAGCGCAGAGCTTTGGCC CCAAAGCUCUGCGCUCCCGdTdT CGGGAGCGCAGAGCUUUGGdTdT n.d. 1243/1244 TOP5464 CAGAGCTTTGGCCCCCAGGCAGC UGCCUGGGGGCCAAAGCUCdTdT GAGCUUUGGCCCCCAGGCAdTdT n.d. 1245/1246 TOP5465 CAGGCAGCATGTCGGCCTTCACT UGAAGGCCGACAUGCUGCCdTdT GGCAGCAUGUCGGCCUUCAdTdT n.d. 1247/1248 TOP5466 CAGCATGTCGGCCTTCACTAGCG CUAGUGAAGGCCGACAUGCdTdT GCAUGUCGGCCUUCACUAGdTdT n.d. 1249/1250 TOP5467 CATGTCGGCCTTCACTAGCGGGA CCGCUAGUGAAGGCCGACAdTdT UGUCGGCCUUCACUAGCGGdTdT n.d. 1251/1252 TOP5468 CACTAGCGGGAGTCCCCCACACC UGUGGGGGACUCCCGCUAGdTdT CUAGCGGGAGUCCCCCACAdTdT n.d. 1253/1254 TOP5469 GATCAAGAACCTAGACCAG CUGGUCUAGGUUCUUGAUCdtdt GAUCAAGAACCUAGACCAGdtdt n.d. 1255/1256 TOP5470 CAGCCGCTTCCCTGAGCTGGAGG UCCAGCUCAGGGAAGCGGCdTdT GCCGCUUCCCUGAGCUGGAdTdT n.d. 1257/1258 TOP5471 GGGTGTTCCCTGTAGGATT AAUCCUAGAGGGAACACCCdtdt GGGUGUUCCCUGUAGGAUUdtdt n.d. 1259/1260 TOP5472 GACAGCGAGGTGTCACCTCTCAC GAGAGGUGACACCUCGCUGdTdT CAGCGAGGUGUCACCUCUCdTdT n.d. 1261/1262 TOP5473 CAGCGAGGTGTCACCTCTCACCA GUGAGAGGUGACACCUCGCdTdT GCGAGGUGUCACCUCUCACdTdT n.d. 1263/1264 TOP5474 GAGGTGTCACCTCTCACCATAGA UAUGGUGAGAGGUGACACCdTdT GGUGUCACCUCUCACCAUAdTdT n.d. 1265/1266 TOP5475 CACCTCTCACCATAGAGGACCCC GGUCCUCUAUGGUGAGAGGdTdT CCUCUCACCAUAGAGGACCdTdT n.d. 1267/1268 TOP5476 CACCATAGAGGACCCCAAGCATG UGCUUGGGGUCCUCUAUGGdTdT CCAUAGAGGACCCCAAGCAdTdT n.d. 1269/1270 TOP5477 CATAGAGGACCCCAAGCATGTCT ACAUGCUUGGGGUCCUCUAdTdT UAGAGGACCCCAAGCAUGUdTdT n.d. 1271/1272 TOP5478 TAGAGGACCCCAAGCATGTCTGT AGACAUGCUUGGGGUCCUCdTdT GAGGACCCCAAGCAUGUCUdTdT n.d. 1273/1274 TOP5479 GAGGACCCCAAGCATGTCTGTGA ACAGACAUGCUUGGGGUCCdTdT GGACCCCAAGCAUGUCUGUdTdT n.d. 1275/1276 TOP5480 GACCCCAAGCATGTCTGTGATCC AUCACAGACAUGCUUGGGGdTdT CCCCAAGCAUGUCUGUGAUdTdT n.d. 1277/1278 TOP5481 CAAGCATGTCTGTGATCCACCAT GGUGGAUCACAGACAUGCUdTdT AGCAUGUCUGUGAUCCACCdTdT n.d. 1279/1280 TOP5482 AAGCATGTCTGTGATCCACCATC UGGUGGAUCACAGACAUGCdTdT GCAUGUCUGUGAUCCACCAdTdT n.d. 1281/1282 TOP5483 CATGTCTGTGATCCACCATCTGG AGAUGGUGGAUCACAGACAdTdT UGUCUGUGAUCCACCAUCUdTdT n.d. 1283/1284 TOP5484 GATCCACCATCTGGGCCTGACAC GUCAGGCCCAGAUGGUGGAdTdT UCCACCAUCUGGGCCUGACdTdT n.d. 1285/1286 TOP5485 CACCATCTGGGCCTGACACGACT UCGUGUCAGGCCCAGAUGGdTdT CCAUCUGGGCCUGACACGAdTdT n.d. 1287/1288 TOP5486 CATCTGGGCCTGACACGACTCCA GAGUCGUGUCAGGCCCAGAdTdT UCUGGGCCUGACACGACUCdTdT n.d. 1289/1290 TOP5487 GACACGACTCCAGCTGCCTCAGA UGAGGCAGCUGGAGUCGUGdTdT CACGACUCCAGCUGCCUCAdTdT n.d. 1291/1292 TOP5488 CACGACTCCAGCTGCCTCAGATC UCUGAGGCAGCUGGAGUCGdTdT CGACUCCAGCUGCCUCAGAdTdT n.d. 1293/1294 TOP5489 GACTCCAGCTGCCTCAGATCTAC AGAUCUGAGGCAGCUGGAGdTdT CUCCAGCUGCCUCAGAUCUdTdT n.d. 1295/1296 TOP5490 CAGCTGCCTCAGATCTACCCACA UGGGUAGAUCUGAGGCAGCdTdT GCUGCCUCAGAUCUACCCAdTdT n.d. 1297/1298 TOP5491 CCTCAGATCTACCCACAGA UCUGUGGGUAGAUCUGAGGdtdt CCUCAGAUCUACCCACAGAdtdt n.d. 1299/1300 TOP5492 CAGATCTACCCACAGAGCAGCCC GCUGCUCUGUGGGUAGAUCdTdT GAUCUACCCACAGAGCAGCdTdT n.d. 1301/1302 TOP5493 GATCTACCCACAGAGCAGCCCCC GGGCUGCUCUGUGGGUAGAdTdT UCUACCCACAGAGCAGCCCdTdT n.d. 1303/1304 TOP5494 CTCCCACACACCTGAGAAA UUUCUCAGGUGUGUGGGAGdtdt CUCCCACACACCUGAGAAAdtdt n.d. 1305/1306 TOP5495 CCCACACACCTGAGAAACA UGUUUCUCAGGUGUGUGGGdtdt CCCACACACCUGAGAAACAdtdt n.d. 1307/1308 TOP5496 CACACACCTGAGAAACAGGCTTC AGCCUGUUUCUCAGGUGUGdTdT CACACCUGAGAAACAGGCUdTdT n.d. 1309/1310 TOP5497 CACACCTGAGAAACAGGCTTCCA GAAGCCUGUUUCUCAGGUGdTdT CACCUGAGAAACAGGCUUCdTdT n.d. 1311/1312 TOP5498 CACCTGAGAAACAGGCTTCCAGC UGGAAGCCUGUUUCUCAGGdTdT CCUGAGAAACAGGCUUCCAdTdT n.d. 1313/1314 TOP5499 GAGAAACAGGCTTCCAGCTTTGA AAAGCUGGAAGCCUGUUUCdTdT GAAACAGGCUUCCAGCUUUdTdT n.d. 1315/1316 TOP5500 AGAAACAGGCTTCCAGCTT AAGCUGGAAGCCUGUUUCUdtdt AGAAACAGGCUUCCAGCUUdtdt n.d. 1317/1318 TOP5501 GAAACAGGCTTCCAGCTTTGACT UCAAAGCUGGAAGCCUGUUdTdT AACAGGCUUCCAGCUUUGAdTdT n.d. 1319/1320 TOP5502 AAACAGGCTTCCAGCTTTGACTT GUCAAAGCUGGAAGCCUGUdTdT ACAGGCUUCCAGCUUUGACdTdT n.d. 1321/1322 TOP5503 AACAGGCTTCCAGCTTTGACTTC AGUCAAAGCUGGAAGCCUGdTdT CAGGCUUCCAGCUUUGACUdTdT n.d. 1323/1324 TOP5504 CAGGCTTCCAGCTTTGACTTCAA GAAGUCAAAGCUGGAAGCCdTdT GGCUUCCAGCUUUGACUUCdTdT n.d. 1325/1326 TOP5505 CAGCTTTGACTTCAATGGGCCCT GGCCCAUUGAAGUCAAAGCdTdT GCUUUGACUUCAAUGGGCCdTdT n.d. 1327/1328 TOP5506 GACTTCAATGGGCCCTACCTGGG CAGGUAGGGCCCAUUGAAGdTdT CUUCAAUGGGCCCUACCUGdTdT n.d. 1329/1330 TOP5507 CACAGCCGCTCCCTACCTGACAT GUCAGGUAGGGAGCGGCUGdTdT CAGCCGCUCCCUACCUGACdTdT n.d. 1331/1332 TOP5508 CAGCCGCTCCCTACCTGACATCC AUGUCAGGUAGGGAGCGGCdTdT GCCGCUCCCUACCUGACAUdTdT n.d. 1333/1334 TOP5509 TACCTGACATCCTGGGCCAGCCG GCUGGCCCAGGAUGUCAGGdTdT CCUGACAUCCUGGGCCAGCdTdT n.d. 1335/1336 TOP5510 CACAGGAGGGTGGGAGCCAGAAG UCUGGCUCCCACCCUCCUGdTdT CAGGAGGGUGGGAGCCAGAdTdT n.d. 1337/1338 TOP5511 CAGGAGGGTGGGAGCCAGAAGTC CUUCUGGCUCCCACCCUCCdTdT GGAGGGUGGGAGCCAGAAGdTdT n.d. 1339/1340 TOP5512 GAGGGTGGGAGCCAGAAGTCCCC GGACUUCUGGCUCCCACCCdTdT GGGUGGGAGCCAGAAGUCCdTdT n.d. 1341/1342 TOP5513 GAGCCAGAAGTCCCCACCTCCAG GGAGGUGGGGACUUCUGGCdTdT GCCAGAAGUCCCCACCUCCdTdT n.d. 1343/1344 TOP5514 CAGAAGTCCCCACCTCCAGGGTC CCCUGGAGGUGGGGACUUCdTdT GAAGUCCCCACCUCCAGGGdTdT n.d. 1345/1346 TOP5515 GAAGTCCCCACCTCCAGGGTCCC GACCCUGGAGGUGGGGACUdTdT AGUCCCCACCUCCAGGGUCdTdT n.d. 1347/1348 TOP5516 AAGTCCCCACCTCCAGGGTCCCT GGACCCUGGAGGUGGGGACdTdT GUCCCCACCUCCAGGGUCCdTdT n.d. 1349/1350 TOP5517 CACCTCCAGGGTCCCTGGAGTAC ACUCCAGGGACCCUGGAGGdTdT CCUCCAGGGUCCCUGGAGUdTdT n.d. 1351/1352 TOP5518 CAGGGTCCCTGGAGTACCTGTGT ACAGGUACUCCAGGGACCCdTdT GGGUCCCUGGAGUACCUGUdTdT n.d. 1353/1354 TOP5519 GAGTACCTGTGTCTGCCTGCTGG AGCAGGCAGACACAGGUACdTdT GUACCUGUGUCUGCCUGCUdTdT n.d. 1355/1356 TOP5520 GTACCTGTGTCTGCCTGCT AGCAGGCAGACACAGGUACdtdt GUACCUGUGUCUGCCUGCUdtdt n.d. 1357/1358 TOP5521 CAGGTGCAACTGGTCCCTCTGGC CAGAGGGACCAGUUGCACCdTdT GGUGCAACUGGUCCCUCUGdTdT n.d. 1359/1360 TOP5522 CAACTGGTCCCTCTGGCCCAGGC CUGGGCCAGAGGGACCAGUdTdT ACUGGUCCCUCUGGCCCAGdTdT n.d. 1361/1362 TOP5523 AACTGGTCCCTCTGGCCCAGGCG CCUGGGCCAGAGGGACCAGdTdT CUGGUCCCUCUGGCCCAGGdTdT n.d.

1363/1364 TOP5524 CAGGCGATGGGACCAGGACAGGC CUGUCCUGGUCCCAUCGCCdTdT GGCGAUGGGACCAGGACAGdTdT n.d. 1365/1366 TOP5525 GATGGGACCAGGACAGGCCGTGG ACGGCCUGUCCUGGUCCCAdTdT UGGGACCAGGACAGGCCGUdTdT n.d. 1367/1368 TOP5526 GACCAGGACAGGCCGTGGAAGTG CUUCCACGGCCUGUCCUGGdTdT CCAGGACAGGCCGUGGAAGdTdT n.d. 1369/1370 TOP5527 CAGGACAGGCCGTGGAAGTGGAG CCACUUCCACGGCCUGUCCdTdT GGACAGGCCGUGGAAGUGGdTdT n.d. 1371/1372 TOP5528 GACAGGCCGTGGAAGTGGAGAGA UCUCCACUUCCACGGCCUGdTdT CAGGCCGUGGAAGUGGAGAdTdT n.d. 1373/1374 TOP5529 CAGGCCGTGGAAGTGGAGAGAAG UCUCUCCACUUCCACGGCCdTdT GGCCGUGGAAGUGGAGAGAdTdT n.d. 1375/1376 TOP5530 GCCGTGGAAGTGGAGAGAA UUCUCUCCACUUCCACGGCdtdt GCCGUGGAAGUGGAGAGAAdtdt n.d. 1377/1378 TOP5531 GAAGTGGAGAGAAGGCCGAGCCA GCUCGGCCUUCUCUCCACUdTdT AGUGGAGAGAAGGCCGAGCdTdT n.d. 1379/1380 TOP5532 AAGTGGAGAGAAGGCCGAGCCAG GGCUCGGCCUUCUCUCCACdTdT GUGGAGAGAAGGCCGAGCCdTdT n.d. 1381/1382 TOP5533 CAGGGAGTCCCTCCCTGGAGTCC ACUCCAGGGAGGGACUCCCdTdT GGGAGUCCCUCCCUGGAGUdTdT n.d. 1383/1384 TOP5534 GGCCAAGGGTGGGAGGACA UGUCCUCCCACCCUUGGCCdtdt GGCCAAGGGUGGGAGGACAdtdt n.d. 1385/1386 TOP5535 CAAGGGTGGGAGGACAGGACCAA GGUCCUGUCCUCCCACCCUdTdT AGGGUGGGAGGACAGGACCdTdT n.d. 1387/1388 TOP5536 AAGGGTGGGAGGACAGGACCAAA UGGUCCUGUCCUCCCACCCdTdT GGGUGGGAGGACAGGACCAdTdT n.d. 1389/1390 TOP5537 GAGGACAGGACCAAAAGGACAGC UGUCCUUUUGGUCCUGUCCdTdT GGACAGGACCAAAAGGACAdTdT n.d. 1391/1392 TOP5538 GACAGGACCAAAAGGACAGCCCT GGCUGUCCUUUUGGUCCUGdTdT CAGGACCAAAAGGACAGCCdTdT n.d. 1393/1394 TOP5539 CAGGACCAAAAGGACAGCCCTGT AGGGCUGUCCUUUUGGUCCdTdT GGACCAAAAGGACAGCCCUdTdT n.d. 1395/1396 TOP5540 GACCAAAAGGACAGCCCTGTGGC CACAGGGCUGUCCUUUUGGdTdT CCAAAAGGACAGCCCUGUGdTdT n.d. 1397/1398 TOP5541 CAAAAGGACAGCCCTGTGGCTAT AGCCACAGGGCUGUCCUUUdTdT AAAGGACAGCCCUGUGGCUdTdT n.d. 1399/1400 TOP5542 AAAAGGACAGCCCTGTGGCTATA UAGCCACAGGGCUGUCCUUdTdT AAGGACAGCCCUGUGGCUAdTdT n.d. 1401/1402 TOP5543 AAAGGACAGCCCTGTGGCTATAC AUAGCCACAGGGCUGUCCUdTdT AGGACAGCCCUGUGGCUAUdTdT n.d. 1403/1404 TOP5544 AAGGACAGCCCTGTGGCTATACC UAUAGCCACAGGGCUGUCCdTdT GGACAGCCCUGUGGCUAUAdTdT n.d. 1405/1406 TOP5545 GACAGCCCTGTGGCTATACCCAT GGGUAUAGCCACAGGGCUGdTdT CAGCCCUGUGGCUAUACCCdTdT n.d. 1407/1408 TOP5546 CAGCCCTGTGGCTATACCCATGA AUGGGUAUAGCCACAGGGCdTdT GCCCUGUGGCUAUACCCAUdTdT n.d. 1409/1410 TOP5547 GACACTGAGGACCCTGGAGTGGC CACUCCAGGGUCCUCAGUGdTdT CACUGAGGACCCUGGAGUGdTdT n.d. 1411/1412 TOP5548 CACTGAGGACCCTGGAGTGGCCT GCCACUCCAGGGUCCUCAGdTdT CUGAGGACCCUGGAGUGGCdTdT n.d. 1413/1414 TOP5549 GAGGACCCTGGAGTGGCCTCTGG AGAGGCCACUCCAGGGUCCdTdT GGACCCUGGAGUGGCCUCUdTdT n.d. 1415/1416 TOP5550 GACCCTGGAGTGGCCTCTGGTTA ACCAGAGGCCACUCCAGGGdTdT CCCUGGAGUGGCCUCUGGUdTdT n.d. 1417/1418 TOP5551 CTGGAGTGGCCTCTGGTTA UAACCAGAGGCCACUCCAGdtdt CUGGAGUGGCCUCUGGUUAdtdt n.d. 1419/1420 TOP5552 TGGAGTGGCCTCTGGTTAT AUAACCAGAGGCCACUCCAdtdt UGGAGUGGCCUCUGGUUAUdtdt n.d. 1421/1422 TOP5553 GAGTGGCCTCTGGTTATGTCTCC AGACAUAACCAGAGGCCACdTdT GUGGCCUCUGGUUAUGUCUdTdT n.d. 1423/1424 TOP5554 TATGTCTCCTCTGCAGACCTGGT CAGGUCUGCAGAGGAGACAdTdT UGUCUCCUCUGCAGACCUGdTdT n.d. 1425/1426 TOP5555 CAGACCTGGTATTCACCCCAAAC UUGGGGUGAAUACCAGGUCdTdT GACCUGGUAUUCACCCCAAdTdT n.d. 1427/1428 TOP5556 GACCTGGTATTCACCCCAAACTC GUUUGGGGUGAAUACCAGGdTdT CCUGGUAUUCACCCCAAACdTdT n.d. 1429/1430 TOP5557 TAGTTCCCTCTCTGGGCCTCCCC GGAGGCCCAGAGAGGGAACdTdT GUUCCCUCUCUGGGCCUCCdTdT n.d. 1431/1432 TOP5558 CAGACCAGACCCCCAGCTTATGT AUAAGCUGGGGGUCUGGUCdTdT GACCAGACCCCCAGCUUAUdTdT n.d. 1433/1434 TOP5559 GACCAGACCCCCAGCTTATGTCC ACAUAAGCUGGGGGUCUGGdTdT CCAGACCCCCAGCUUAUGUdTdT n.d. 1435/1436 TOP5560 CAGACCCCCAGCTTATGTCCTGG AGGACAUAAGCUGGGGGUCdTdT GACCCCCAGCUUAUGUCCUdTdT n.d. 1437/1438 TOP5561 GACCCCCAGCTTATGTCCTGGGC CCAGGACAUAAGCUGGGGGdTdT CCCCCAGCUUAUGUCCUGGdTdT n.d. 1439/1440 TOP5562 CAGCTTATGTCCTGGGCTGGCCA GCCAGCCCAGGACAUAAGCdTdT GCUUAUGUCCUGGGCUGGCdTdT n.d. 1441/1442 TOP5563 TATGTCCTGGGCTGGCCAGTGGA CACUGGCCAGCCCAGGACAdTdT UGUCCUGGGCUGGCCAGUGdTdT n.d. 1443/1444 TOP5564 GAGCCCCAGGCCCTGTGAAGTCA ACUUCACAGGGCCUGGGGCdTdT GCCCCAGGCCCUGUGAAGUdTdT n.d. 1445/1446 TOP5565 CAGGCCCTGTGAAGTCAGGGTTT ACCCUGACUUCACAGGGCCdTdT GGCCCUGUGAAGUCAGGGUdTdT n.d. 1447/1448 TOP5566 GAAGTCAGGGTTTGAGGGCTATG UAGCCCUCAAACCCUGACUdTdT AGUCAGGGUUUGAGGGCUAdTdT n.d. 1449/1450 TOP5567 AAGTCAGGGTTTGAGGGCTATGT AUAGCCCUCAAACCCUGACdTdT GUCAGGGUUUGAGGGCUAUdTdT n.d. 1451/1452 TOP5568 CAGGGTTTGAGGGCTATGTGGAG CCACAUAGCCCUCAAACCCdTdT GGGUUUGAGGGCUAUGUGGdTdT n.d. 1453/1454 TOP5569 GAGGGCTATGTGGAGCTCCCTCC AGGGAGCUCCACAUAGCCCdTdT GGGCUAUGUGGAGCUCCCUdTdT n.d. 1455/1456 TOP5570 TATGTGGAGCTCCCTCCAATTGA AAUUGGAGGGAGCUCCACAdTdT UGUGGAGCUCCCUCCAAUUdTdT n.d. 1457/1458 TOP5571 GAGCTCCCTCCAATTGAGGGCCG GCCCUCAAUUGGAGGGAGCdTdT GCUCCCUCCAAUUGAGGGCdTdT n.d. 1459/1460 TOP5572 CAATTGAGGGCCGGTCCCCCAGG UGGGGGACCGGCCCUCAAUdTdT AUUGAGGGCCGGUCCCCCAdTdT n.d. 1461/1462 TOP5573 AATTGAGGGCCGGTCCCCCAGGT CUGGGGGACCGGCCCUCAAdTdT UUGAGGGCCGGUCCCCCAGdTdT n.d. 1463/1464 TOP5574 CAGGTCACCAAGGAACAATCCTG GGAUUGUUCCUUGGUGACCdTdT GGUCACCAAGGAACAAUCCdTdT n.d. 1465/1466 TOP5575 CACCAAGGAACAATCCTGTCCCC GGACAGGAUUGUUCCUUGGdTdT CCAAGGAACAAUCCUGUCCdTdT n.d. 1467/1468 TOP5576 CAAGGAACAATCCTGTCCCCCCT GGGGGACAGGAUUGUUCCUdTdT AGGAACAAUCCUGUCCCCCdTdT n.d. 1469/1470 TOP5577 AAGGAACAATCCTGTCCCCCCTG GGGGGGACAGGAUUGUUCCdTdT GGAACAAUCCUGUCCCCCCdTdT n.d. 1471/1472 TOP5578 GAACAATCCTGTCCCCCCTGAGG UCAGGGGGGACAGGAUUGUdTdT ACAAUCCUGUCCCCCCUGAdTdT n.d. 1473/1474 TOP5579 AACAATCCTGTCCCCCCTGAGGC CUCAGGGGGGACAGGAUUGdTdT CAAUCCUGUCCCCCCUGAGdTdT n.d. 1475/1476 TOP5580 CAATCCTGTCCCCCCTGAGGCCA GCCUCAGGGGGGACAGGAUdTdT AUCCUGUCCCCCCUGAGGCdTdT n.d. 1477/1478 TOP5581 AATCCTGTCCCCCCTGAGGCCAA GGCCUCAGGGGGGACAGGAdTdT UCCUGUCCCCCCUGAGGCCdTdT n.d. 1479/1480 TOP5582 GAGGCCAAAAGCCCTGTCCTGAA CAGGACAGGGCUUUUGGCCdTdT GGCCAAAAGCCCUGUCCUGdTdT n.d. 1481/1482 TOP5583 CAAAAGCCCTGTCCTGAACCCAG GGGUUCAGGACAGGGCUUUdTdT AAAGCCCUGUCCUGAACCCdTdT n.d. 1483/1484 TOP5584 AAAAGCCCTGTCCTGAACCCAGG UGGGUUCAGGACAGGGCUUdTdT AAGCCCUGUCCUGAACCCAdTdT n.d. 1485/1486 TOP5585 AAAGCCCTGTCCTGAACCCAGGG CUGGGUUCAGGACAGGGCUdTdT AGCCCUGUCCUGAACCCAGdTdT n.d. 1487/1488 TOP5586 GAACGCCCGGCAGATGTGTCCCC GGACACAUCUGCCGGGCGUdTdT ACGCCCGGCAGAUGUGUCCdTdT n.d. 1489/1490 TOP5587 AACGCCCGGCAGATGTGTCCCCA GGGACACAUCUGCCGGGCGdTdT CGCCCGGCAGAUGUGUCCCdTdT n.d. 1491/1492 TOP5588 CAGATGTGTCCCCAACATCCCCA GGGAUGUUGGGGACACAUCdTdT GAUGUGUCCCCAACAUCCCdTdT n.d. 1493/1494 TOP5589 GATGTGTCCCCAACATCCCCACA UGGGGAUGUUGGGGACACAdTdT UGUGUCCCCAACAUCCCCAdTdT n.d. 1495/1496 TOP5590 CAACATCCCCACAGCCCGAGGGC CCUCGGGCUGUGGGGAUGUdTdT ACAUCCCCACAGCCCGAGGdTdT n.d. 1497/1498 TOP5591 AACATCCCCACAGCCCGAGGGCC CCCUCGGGCUGUGGGGAUGdTdT CAUCCCCACAGCCCGAGGGdTdT n.d. 1499/1500 TOP5592 GAGGGCCTCCTTGTCCTGCAGCA CUGCAGGACAAGGAGGCCCdTdT GGGCCUCCUUGUCCUGCAGdTdT n.d. 1501/1502 TOP5593 GCAGCAAGTGGGCGACTAT AUAGUCGCCCACUUGCUGCdtdt GCAGCAAGUGGGCGACUAUdtdt n.d. 1503/1504 TOP5594 CAGCAAGTGGGCGACTATTGCTT GCAAUAGUCGCCCACUUGCdTdT GCAAGUGGGCGACUAUUGCdTdT n.d. 1505/1506 TOP5595 CAAGTGGGCGACTATTGCTTCCT GAAGCAAUAGUCGCCCACUdTdT AGUGGGCGACUAUUGCUUCdTdT n.d. 1507/1508 TOP5596 AAGTGGGCGACTATTGCTTCCTC GGAAGCAAUAGUCGCCCACdTdT GUGGGCGACUAUUGCUUCCdTdT n.d. 1509/1510 TOP5597 GACTATTGCTTCCTCCCCGGCCT GCCGGGGAGGAAGCAAUAGdTdT CUAUUGCUUCCUCCCCGGCdTdT n.d. 1511/1512 TOP5598 TATTGCTTCCTCCCCGGCCTGGG CAGGCCGGGGAGGAAGCAAdTdT UUGCUUCCUCCCCGGCCUGdTdT n.d. 1513/1514 TOP5599 GAGTAAACCTTCTTCCCCGGGAC CCCGGGGAAGAAGGUUUACdTdT GUAAACCUUCUUCCCCGGGdTdT n.d. 1515/1516 TOP5600 TAAACCTTCTTCCCCGGGACCCG GGUCCCGGGGAAGAAGGUUdTdT AACCUUCUUCCCCGGGACCdTdT n.d. 1517/1518 TOP5601 AAACCTTCTTCCCCGGGACCCGG GGGUCCCGGGGAAGAAGGUdTdT ACCUUCUUCCCCGGGACCCdTdT n.d. 1519/1520 TOP5602 AACCTTCTTCCCCGGGACCCGGT CGGGUCCCGGGGAAGAAGGdTdT CCUUCUUCCCCGGGACCCGdTdT n.d. 1521/1522 TOP5603 GACCCGGTCCTGAGATCAAGAAC UCUUGAUCUCAGGACCGGGdTdT CCCGGUCCUGAGAUCAAGAdTdT n.d. 1523/1524 TOP5604 GAGATCAAGAACCTAGACCAGGC CUGGUCUAGGUUCUUGAUCdTdT GAUCAAGAACCUAGACCAGdTdT n.d. 1525/1525 TOP5605 GATCAAGAACCTAGACCAGGCTT GCCUGGUCUAGGUUCUUGAdTdT UCAAGAACCUAGACCAGGCdTdT n.d. 1527/1528 TOP5606 CAAGAACCTAGACCAGGCTTTTC AAAGCCUGGUCUAGGUUCUdTdT AGAACCUAGACCAGGCUUUdTdT n.d. 1529/1530 TOP5607 AAGAACCTAGACCAGGCTTTTCA AAAAGCCUGGUCUAGGUUCdTdT

GAACCUAGACCAGGCUUUUdTdT n.d. 1531/1532 TOP5608 GAACCTAGACCAGGCTTTTCAAG UGAAAAGCCUGGUCUAGGUdTdT ACCUAGACCAGGCUUUUCAdTdT n.d. 1533/1534 TOP5609 AACCTAGACCAGGCTTTTCAAGT UUGAAAAGCCUGGUCUAGGdTdT CCUAGACCAGGCUUUUCAAdTdT n.d. 1535/1536 TOP5610 TAGACCAGGCTTTTCAAGTCAAG UGACUUGAAAAGCCUGGUCdTdT GACCAGGCUUUUCAAGUCAdTdT n.d. 1537/1538 TOP5611 GACCAGGCTTTTCAAGTCAAGAA CUUGACUUGAAAAGCCUGGdTdT CCAGGCUUUUCAAGUCAAGdTdT n.d. 1539/1540 TOP5612 CAGGCTTTTCAAGTCAAGAAGCC CUUCUUGACUUGAAAAGCCdTdT GGCUUUUCAAGUCAAGAAGdTdT n.d. 1541/1542 TOP5613 CAAGTCAAGAAGCCCCCAGGCCA GCCUGGGGGCUUCUUGACUdTdT AGUCAAGAAGCCCCCAGGCdTdT n.d. 1543/1544 TOP5614 AAGTCAAGAAGCCCCCAGGCCAG GGCCUGGGGGCUUCUUGACdTdT GUCAAGAAGCCCCCAGGCCdTdT n.d. 1545/1546 TOP5615 AAGAAGCCCCCAGGCCAGGCTGT AGCCUGGCCUGGGGGCUUCdTdT GAAGCCCCCAGGCCAGGCUdTdT n.d. 1547/1548 TOP5616 CAGGTGCCCGTCATTCAGCTCTT GAGCUGAAUGACGGGCACCdTdT GGUGCCCGUCAUUCAGCUCdTdT n.d. 1549/1550 TOP5617 CCGTCATTCAGCTCTTCAA UUGAAGAGCUGAAUGACGGdtdt CCGUCAUUCAGCUCUUCAAdtdt n.d. 1551/1552 TOP5618 CATTCAGCTCTTCAAAGCCCTGA AGGGCUUUGAAGAGCUGAAdTdT UUCAGCUCUUCAAAGCCCUdTdT n.d. 1553/1554 TOP5619 CAGCTCTTCAAAGCCCTGAAGCA CUUCAGGGCUUUGAAGAGCdTdT GCUCUUCAAAGCCCUGAAGdTdT n.d. 1555/1556 TOP5620 CAAAGCCCTGAAGCAGCAGGACT UCCUGCUGCUUCAGGGCUUdTdT AAGCCCUGAAGCAGCAGGAdTdT n.d. 1557/1558 TOP5621 AAAGCCCTGAAGCAGCAGGACTA GUCCUGCUGCUUCAGGGCUdTdT AGCCCUGAAGCAGCAGGACdTdT n.d. 1559/1560 TOP5622 AAGCCCTGAAGCAGCAGGACTAC AGUCCUGCUGCUUCAGGGCdTdT GCCCUGAAGCAGCAGGACUdTdT n.d. 1561/1562 TOP5623 GAAGCAGCAGGACTACCTGTCTC GACAGGUAGUCCUGCUGCUdTdT AGCAGCAGGACUACCUGUCdTdT n.d. 1563/1564 TOP5624 AAGCAGCAGGACTACCTGTCTCT AGACAGGUAGUCCUGCUGCdTdT GCAGCAGGACUACCUGUCUdTdT n.d. 1565/1566 TOP5625 CAGCAGGACTACCTGTCTCTGCC CAGAGACAGGUAGUCCUGCdTdT GCAGGACUACCUGUCUCUGdTdT n.d. 1567/1568 TOP5626 CAGGACTACCTGTCTCTGCCCCC GGGCAGAGACAGGUAGUCCdTdT GGACUACCUGUCUCUGCCCdTdT n.d. 1569/1570 TOP5627 GACTACCTGTCTCTGCCCCCTTG AGGGGGCAGAGACAGGUAGdTdT CUACCUGUCUCUGCCCCCUdTdT n.d. 1571/1572 TOP5628 TACCTGTCTCTGCCCCCTTGGGA CCAAGGGGGCAGAGACAGGdTdT CCUGUCUCUGCCCCCUUGGdTdT n.d. n.d.: not-determined

TABLE-US-00004 TABLE 2b SEQ ID Nos CCR3 (antisense/ si RNA ID Target Antisense strand mRNA sense) NUMBER sequence (5'-3') (5'-3') Sense strand (5'-3') Inhibition 1573/1574 ¹siCCR3_1HP CCGAATTATGACCAACATCTA UAGAUGUUGGUCAUAAUUCgg GAAUUAUGACCAACAUCUAtt >40% 1575/1576 ²siCCR3_1137 AAGGCCATCCGGCTCATTTTT AAAAAUGAGCCGGAUGG AAGGCCAUCCGGCUCAUUUUUtt 20-40% CCUUtt 1577/1578 ²siCCR3_1320 AACCCGGTGATCTACGCCTTT AAAGGCGUAGAUCACCG AACCCGGUGAUCUACGCCUUUtt 20-40% GGUUtt RNA: UPPER CASE; dna: lower case ¹Designed by Qiagen HP OnGuard siRNA Design (Genome Wide) ²Designed using Qiagen siRNA design tool (standard Tuschl-based design) Thermo scientific Dharmacon RNAi Technologies siDESIGN Center (Custom siRNA Design Tool). www.thermo.com/sidesign Invitrogen (BLOCK-I^Tm RNAi Designer). https://rnaidesigner.invitrogen.com EMBOSS https://anabench.bcm.umontreal.ca/html/EMBOSS/runs/file6LGF4f/index- .html

TABLE-US-00005 TABLE 3a β-chain β-chain Relative Seq ID Antisense Sequence mRNA protein stability in number ID (5'-3') inhibition inhibition 50% FBS 1579 TOP057-F1 PS-GAccgagctggccacCTCC - n.d. n.d. 1580 TOP057-F2 PS-GACcgagCTGgccaccTCC - n.d. n.d. 1581 TOP062-F1 PS-CTCTCCacttccacGGCCTG - n.d. + 1582 TOP062-F2 PS-CTctccacttccacggCCTG = = + 1583 TOP062-F3 PS-ctctccacttccacggCCTG = + - 1584 TOP062-F4 PS-CTCtccacttccacggcCTG = = - 1585 TOP062-F5 PS-CTctccaCTTccacggCCTG = n.d. - 1586 TOP062-F6 PS-CtCtCcacttccacgGcCtG = n.d. + 1587 TOP062-F7 PS-ctctccaCTTCCAcggcctg = = + 1588 TOP062-F8 PS-ctctcCACL ttccACGgcctg = - + 1589 TOP062-F9 ctctcCACttccACGgcctg - n.d. - 1590 TOP062-F10 CTCtccacttccacggcCTG - n.d. - 1591 TOP062-F11 PS-cTcTcCaCtTcCaCgGcCtG - n.d. + 1592 TOP062-F12 PS-CTctCCacTTccACggCCTG - n.d. - 1593 TOP062-F13 ctctcCActtccaCGgcctg = n.d. n.d. 1594 TOP062-F14 ctctcCACttccACGgcctg = n.d. n.d. 1595 TOP062-F15 ctctcCACttccACGgcctg = n.d. n.d. 1596 TOP062-F16 ctctccaCTTCCAcggcctg = n.d. n.d. 1597 TOP062-F17 ctctccaCTTCCAcggcctg = n.d. n.d. 1598 TOP062-F18 ctctccaCTTCCAcggcctg = n.d. n.d. Lower case letters = DNA; BOLD UPPERCASE LETTERS = 2'F-ANA Phosphodiester linkage = underlined; All phosphorothioate linkages = prefix PS- (+/-): efficacy or stability greater/lower than corresponding PS-DNA (=): efficacy or stability equal to corresponding PS-DNA n.d.: not-determined

TABLE-US-00006 TABLE 3b Relative Seq ID Antisense Sequence CCR3 mRNA CCR3 protein stability in number ID (5'-3') inhibition inhibition 50% FBS 1599 TOP030-F1 PS-CACCTCtgtcaccAGCATG = = + 1600 TOP030-F2 PS-CACCTCTGtcaccagCATG = = + 1601 TOP030-F3 PS-CACCTgTGTCaccagcaTG - n.d. + 1602 TOP030-F4 PS-cacctctgtcaccagcATG = = - 1603 TOP030-F5 PS-CAcctctgtcaccagcATG = = - 1604 TOP030-F6 PS-CACCtctgtcaccagCATG = = - 1605 TOP030-F7 PS-CACCtctGTcaccagCATG = = + 1606 TOP030-F8 PS-CaCcTcTgTcAcCaGcAtG - n.d. + 1607 TOP030-F9 PS-CAccTCtgTCacCAgcATG - n.d. - 1608 TOP030-F10 CACCTCTGtcaccagCATG - n.d. n.d. 1609 TOP030-F11 CACCTCTGtcaccagCATG - n.d. n.d. 1610 TOP030-F12 CACCTCTGtcaccagCATG = + n.d. 1611 TOP030-F13 CACCTCTGtcaccagCATG - n.d. n.d. 1612 TOP030-F14 PS-CACCTCtgtcaccagCATG = = n.d. 1613 TOP030-F15 CACCTCTGtcaccagCATG - n.d. n.d. 1614 TOP030-F16 CACCTCTGtcaccagCATG - n.d. n.d. 1615 TOP030-F17 CACCTCTGtcdccdgCATG - n.d. 1616 TOP030-F18 CACCTCtgtcaccagCATG n.d. n.d. n.d. 1617 TOP038-F1 PS-GAatgggatgtatctGCCCA - n.d. n.d. 1618 TOP038-F2 PS-GAatgggatgTAtctgcCCA - n.d. n.d. 1619 TOP042-F1 PS-ACcaggtccagatgcTTGCT - n.d. n.d. 1620 TOP042-F2 PS-ACcaggtcCAgatgcttGCT - n.d. n.d. Lower case letters = DNA; BOLD UPPERCASE LETTERS = 2'F-ANA; d = DAP Phosphodiester linkage = underlined; All phosphorothioate linkages = prefix PS- (+/-): efficacy or stability greater/lower than corresponding PS-DNA (=): efficacy or stability equal to corresponding PS-DNA; n.d.: not-determined

TABLE-US-00007 TABLE 3c β-chain Seq AON AON sequence mRNA ID ID (5'-3') Inhibition 1621 TOP062-DAP ctctccdcttccdcggcctg = 1622 TOP057-DAP gdccgdgctggccdcctcc = 1623 TOP073-DAP tccdctggccdgcccdggdc = 1624 TOP077-DAP ddgdgtcctgddgccgcttgt = 1625 TOP206-DAP dtdgccdcdgggctgtcctt n.d. Lower case letters = DNA All phosphorothioate linkages d = 2-amino-2'-deoxyadenosine (=): efficacy equal to corresponding PS-DNA; n.d.: not-determined

TABLE-US-00008 TABLE 4 Target Seq ID Antisense Sequence gene number ID (5'-3') Rat β- 1626 TOP006 tggcactttaggtggctg chain 1627 TOP006-F2 TGgcactttaggtGGCTG Rat CCR3 1628 TOP007 actcatattcatagggtg 1629 TOP007-F8 ACtcatattcatagGGTG All phosphorothioate linkages Lower case letters = DNA; BOLD UPPERCASE LETTERS = 2'F-ANA

TABLE-US-00009 TABLE 5 TPI ASM8 25 TPI 1100 (mg/kg/day) (mg/kg/day) Recovery Recovery Main (Day 15) (Day 29) Main (Day 15) (Day 42) 0 0.05 0.25 2.5 0 2.5 0 0.05 0.25 2.5 0 2.5 Lung Accumulation of macrophages, foamy: minimal 3/6 2/6 1/2 3/6 mild 4/6 3/6 Macrophage Accumulation, alveolar, non- foamy: minimal 3/6 mild 3/6 Inflammation, intra-alveolar, granulocytic: minimal 2/6 Metaplasia, bronchilar: minimal 1/6 Haemorrhage, focal: minimal 1/6 mild 1/6 Lymph node, bronchial Accumulation of macrophages, foamy: minimal 6/6 2/2 1/6 Histiocytosis, sinus: minimal 1/6 1/6 2/6 2/4 mild 4/6 1/4

[0208] Values represent number of animals in which change was observed per number of animals examined.

TABLE-US-00010 TABLE 6 TPI ASM8 and TPI 1100 SEQ ID Name Length Target Sequence 5'-3' NO. TPI ASM8 TOP004 19 Hu βc GGGTCTGCDGCGGGDTGGT 1630 TOP005 21 Hu CCR3 GTTDCTDCTTCCDCCTGCCTG 1631 TPI 1100 TOP1572 19 Hu PDE4B/ GGTTGCTCAGITCTGCACA 1632 4D TOP1731 21 Hu PDE7A TCATGAGTGGCAGCTGCAATT 1633 All phosphorothioate linkages. Uppercase letters = DNA; Bold italic letters = FANA; I = Inosine; D = 2,amino-2'-deoxyadenosine

TABLE-US-00011 TABLE 7 β- chain SEQ ID Nos 5p strand 3p strand inhi- 5p/3p strand miRNA mimic miRNA (5'-3') (5'-3') bition 1634/1635 ^1,2TOP5119 hsa-miR-493 UUGUACAUGGUAGGCUUUCAUU UGAAGGUCUACUGUGUGCCAGG n.d. 1636/1637 ^2,3TOP5120 hsa-miR-502 AUCCUUGCUAUCUGGGUGCUA AAUGCACCUGGGCAAGGAUUCA >40% 1638/1639 ^1,2,3TOP5121 hsa-miR-576 AUUCUAAUUUCUCCACGUCUUU AAGAUGUGGAAAAAUUGGAAUC >40% 1640/1641 ^2,3,4TOP5122 hsa-miR-548b AAAAGUAAUUGUGGUUUUGGCC CAAGAACCUCAGUUGCUUUUGU >40% 1642/1643 ^1,2TOP5123 hsa-miR-136 ACUCCAUUUGUUUUGAUGAUGGA CAUCAUCGUCUCAAAUGAGUCU >40% 1644/1645 ²TOP5124 hsa-miR-129 CUUUUUGCGGUCUGGGCUUGC AAGCCCUUACCCCAAAAAGCAU >40% 1646/1647 ^1,2TOP5125 hsa-miR-185 UGGAGAGAAAGGCAGUUCCUGA AGGGGCUGGCUUUCCUCUGGUC n.d. 1648/NA ^1,3TOP5126 hsa-miR-298 AGCAGAAGCAGGGAGGUUCUCCCA NA n.d. 1649/1650 ^1,2TOP5127 hsa-miR-324-3p CGCAUCCCCUAGGGCAUUGGUGU ACUGCCCCAGGUGCUGCUGG n.d. 1651/1652 ¹TOP5128 hsa-miR-339-3p UCCCUGUCCUCCAGGAGCUCACG UGAGCGCCUCGACGACAGAGCCG n.d. 1653/1654 ^1,2TOP5129 hsa-miR-485-5p AGAGGCUGGCCCUGAUGAAUUC GUCAUACACGGCUCUCCUCUCU n.d. 1655/1656 ¹TOP5130 hsa-miR-490-3p CCAUGGAUCUCCAGGUGGGU CAACCUGGAGGACUCCAUGCUG n.d. 1657/1658 ¹TOP5131 hsa-miR-628-5p AUGCUGACAUAUUUACUAGAGG UCUAGUAAGAGUGGCAGUCGA n.d. NA/1659 ^1,3TOP5132 hsa-miR-637 NA ACUGGGGGCUUUCGGGCUCUGCGU n.d. NA/1660 ¹TOP5133 hsa-miR-645 NA UCUAGGCUGGUACUGCUGA n.d. NA/1661 ¹TOP5134 hsa-miR-649 NA AAACCUGUGUUGUUCAAGAGUC n.d. NA/1662 ^1,3TOP5135 hsa-miR-661 NA UGCCUGGGUCUCUGGCCUGCGCGU n.d. 1663/NA ¹TOP5136 hsa-miR-1203 CCCGGAGCCAGGAUGCAGCUC NA n.d. 1664/NA ¹TOP5137 hsa-miR-1251 ACUCUAGCUGCCAAAGGCGCU NA n.d. 1665/NA ¹TOP5138 hsa-miR-1283 UCUACAAAGGAAAGCGCUUUCU NA n.d. 1666/1667 ²TOP5139 hsa-miR-19a AGUUUUGCAUAGUUGCACUACA UGUGCAAAUCUAUGCAAAACUGA n.d. 1668/1669 ²TOP5140 hsa-miR-20a UAAAGUGCUUAUAGUGCAGGUAG ACUGCAUUAUGAGCACUUAAAG n.d. 1670/1671 ²TOP5141 hsa-miR-20b CAAAGUGCUCAUAGUGCAGGUAG ACUGUAGUAUGGGCACUUCCAG n.d. 1672/1673 ²TOP5142 hsa-miR-27b AGAGCUUAGCUGAUUGGUGAAC UUCACAGUGGCUAAGUUCUGC n.d. 1674/1675 ²TOP5143 hsa-miR-106b UAAAGUGCUGACAGUGCAGAU CCGCACUGUGGGUACUUGCUGC n.d. 1676/1677 ²TOP5144 hsa-miR-127-5p CUGAAGCUCAGAGGGCUCUGAU UCGGAUCCGUCUGAGCUUGGCU n.d. 1678/NA ²TOP5145 hsa-miR-134 UGUGACUGGUUGACCAGAGGGG NA n.d. 1679/1680 ²TOP5146 hsa-miR-138-2 AGCUGGUGUUGUGAAUCAGGCCG GCUAUUUCACGACACCAGGGUU n.d. 1681/1682 ²TOP5147 hsa-miR-148a AAAGUUCUGAGACACUCCGACU UCAGUGCACUACAGAACUUUGU n.d. 1683/1684 ²TOP5148 hsa-miR-149 UCUGGCUCCGUGUCUUCACUCCC AGGGAGGGACGGGGGCUGUGC n.d. 1685/1686 ²TOP5149 hsa-miR-154 UAGGUUAUCCGUGUUGCCUUCG AAUCAUACACGGUUGACCUAUU n.d. 1687/1688 ²TOP5150 hsa-miR-155 UUAAUGCUAAUCGUGAUAGGGGU CUCCUACAUAUUAGCAUUAACA n.d. 1689/1690 ²TOP5151 hsa-miR-182 UUUGGCAAUGGUAGAACUCACACU UGGUUCUAGACUUGCCAACUA n.d. 1691/1692 ²TOP5152 hsa-miR-188-5p CAUCCCUUGCAUGGUGGAGGG CUCCCACAUGCAGGGUUUGCA n.d. 1693/NA ^2,3TOP5153 hsa-miR-204 UUCCCUUUGUCAUCCUAUGCCU NA n.d. 1694/NA ^2,3TOP5154 hsa-miR-211 UUCCCUUUGUCAUCCUUCGCCU NA n.d. 1695/1696 ²TOP5155 hsa-miR-214 UGCCUGUCUACACUUGCUGUGC ACAGCAGGCACAGACAGGCAGU n.d. NA/1697 ²TOP5156 hsa-miR-328 NA CUGGCCCUCUCUGCCCUUCCGU n.d. 1698/NA ²TOP5157 hsa-miR-345 GCUGACUCCUAGUCCAGGGCUC NA n.d. 1699/1700 ²TOP5158 hsa-miR-377 AGAGGUUGCCCUUGGUGAAUUC AUCACACAAAGGCAACUUUUGU n.d. NA/1701 ²TOP5159 hsa-miR-453 NA AGGUUGUCCGUGGUGAGUUCGCA n.d. 1702/1703 ²TOP5160 hsa-miR-483-5p AAGACGGGAGGAAAGAAGGGAG UCACUCCUCUCCUCCCGUCUU n.d. 1704/NA ²TOP5161 hsa-miR-573 CUGAAGUGAUGUGUAACUGAUCAG NA n.d. NA/1705 ²TOP5162 hsa-miR-600 NA ACUUACAGACAAGAGCCUUGCUC n.d. 1706/NA ²TOP5163 hsa-miR-601 UGGUCUAGGAUUGUUGGAGGAG NA n.d. NA/1707 ²TOP5164 hsa-miR-633 NA CUAAUAGUAUCUACCACAAUAAA n.d. 1708/NA ^2,3TOP5165 hsa-miR-650 AGGAGGCAGCGCUCUCAGGAC NA n.d. NA/1709 ²TOP5166 hsa-miR-657 NA GGCAGGUUCUCACCCUCUCUAGG n.d. NA/1710 ^2,3TOP5167 hsa-miR-658 NA GGCGGAGGGAAGUAGGUCCGUUGGU n.d. 1711/NA ²TOP5168 hsa-miR-663 AGGCGGGGCGCCGCGGGACCGC NA n.d. 1712/1713 ²TOP5169 hsa-miR-877 GUAGAGGAGAUGGCGCAGGG UCCUCUUCUCCCUCCUCCCAG n.d. 1714/1715 ²TOP5170 hsa-miR-886-5p CGGGUCGGAGUUAGCUCAAGCGG CGCGGGUGCUUACUGACCCUU n.d. NA/1716 ²TOP5171 hsa-miR-940 NA AAGGCAGGGCCCCCGCUCCCC n.d. 1717/1718 ³TOP5172 hsa-miR-32 UAUUGCACAUUACUAAGUUGCA CAAUUUAGUGUGUGUGAUAUUU n.d. NA/1719 ³TOP5173 hsa-miR-137 NA UUAUUGCUUAAGAAUACGCGUAG n.d. 1720/1721 ³TOP5174 hsa-miR-142-5p CAUAAAGUAGAAAGCACUACU UGUAGUGUUUCCUACUUUAUGGA n.d. 1722/1723 ³TOP5175 hsa-miR-181a AACAUUCAACGCUGUCGGUGAGU ACCAUCGACCGUUGAUUGUACC n.d. NA/1724 ³TOP5176 hsa-miR-181b AACAUUCAUUGCUGUCGGUGGGU NA n.d. 1725/1726 ^3,4TOP5177 hsa-miR-181c AACAUUCAACCUGUCGGUGAGU AACCAUCGACCGUUGAGUGGAC n.d. 1727/NA ³TOP5178 hsa-miR-181d AACAUUCAUUGUUGUCGGUGGGU NA n.d. NA/1728 ³TOP5179 hsa-miR-300 NA UAUACAAGGGCAGACUCUCUCU n.d. 1729/1730 ³TOP5180 hsa-miR-335 UCAAGAGCAAUAACGAAAAAUGU UUUUUCAUUAUUGCUCCUGACC n.d. 1731/1732 ³TOP5181 hsa-miR-337-3p GAACGGCUUCAUACAGGAGUU CUCCUAUAUGAUGCCUUUCUUC n.d. 1733/1734 ³TOP5182 hsa-miR-376a GUAGAUUCUCCUUCUAUGAGUA AUCAUAGAGGAAAAUCCACGU n.d. NA/1735 ³TOP5183 hsa-miR-376b NA AUCAUAGAGGAAAAUCCAUGUU n.d. NA/1736 ³TOP5184 hsa-miR-381 NA UAUACAAGGGCAAGCUCUCUGU n.d. 1737/NA ³TOP5185 hsa-miR-382 GAAGUUGUUCGUGGUGGAUUCG NA n.d. 1738/1739 ³TOP5186 hsa-miR-409-3p AGGUUACCCGAGCAACUUUGCAU GAAUGUUGCUCGGUGAACCCCU n.d. 1740/1741 ³TOP5187 hsa-miR-450b-3p UUUUGCAAUAUGUUCCUGAAUA UUGGGAUCAUUUUGCAUCCAUA n.d. 1742/NA ³TOP5188 hsa-miR-513b UUCACAAGGAGGUGUCAUUUAU NA n.d. 1743/1744 ³TOP5189 hsa-miR-522 CUCUAGAGGGAAGCGCUUUCUG AAAAUGGUUCCCUUUAGAGUGU n.d. NA/1745 ³TOP5190 hsa-miR-543 NA AAACAUUCGCGGUGCACUUCUU n.d. 1746/1747 ³TOP5191 hsa-miR-548a-5p AAAAGUAAUUGCGAGUUUUACC CAAAACUGGCAAUUACUUUUGC n.d. 1748/1749 ³TOP5192 hsa-miR-548c-5p AAAAGUAAUUGCGGUUUUUGCC CAAAAAUCUCAAUUACUUUUGC n.d. 1750/1751 ³TOP5193 hsa-miR-548d-5p AAAAGUAAUUGUGGUUUUUGCC CAAAAACCACAGUUUCUUUUGC n.d. 1752/NA ³TOP5194 hsa-miR-548h AAAAGUAAUCGCGGUUUUUGUC NA n.d. 1753/NA ³TOP5195 hsa-miR-548i AAAAGUAAUUGCGGAUUUUGCC NA n.d. 1754/NA ³TOP5196 hsa-miR-548j AAAAGUAAUUGCGGUCUUUGGU NA n.d. 1755/NA ³TOP5197 hsa-miR-5481 AAAAGUAUUUGCGGGUUUUGUC NA n.d. 1756/NA ³TOP5198 hsa-miR-548n CAAAAGUAAUUGUGGAUUUUGU NA n.d. NA/1757 ³TOP5199 hsa-miR-548p NA UAGCAAAAACUGCAGUUACUUU n.d. NA/1758 ³TOP5200 hsa-miR-570 NA CGAAAACAGCAAUUACCUUUGC n.d. 1759/NA ³TOP5201 hsa-miR-559 UAAAGUAAAUAUGCACCAAAA NA n.d. 1760/NA ³TOP5202 hsa-miR-641 AAAGACAUAGGAUAGAGUCACCUC NA n.d. 1761/1762 ³TOP5203 hsa-miR-654-3p UGGUGGGCCGCAGAACAUGUGC UAUGUCUGCUGACCAUCACCUU n.d. NA/1763 ³TOP5204 hsa-miR-659 NA CUUGGUUCAGGGAGGGUCCCCA n.d. 1764/1765 ³TOP5205 hsa-miR-671-5p AGGAAGCCCUGGAGGGGCUGGAG UCCGGUUCUCAGGGCUCCACC n.d. 1766/NA ³TOP5206 hsa-miR-802 CAGUAACAAAGAUUCAUCCUUGU NA n.d. 1767/1768 ³TOP5207 hsa-miR-876-5p UGGAUUUCUUUGUGAAUCACCA UGGUGGUUUACAAAGUAAUUCA n.d. NA/1769 ³TOP5208 hsa-miR-889 NA UUAAUAUCGGACAACCAUUGU n.d. 1770/NA ³TOP5209 hsa-miR-1231 GUGUCUGGGCGGACAGCUGC NA n.d. NA/1771 ³TOP5210 hsa-miR-1233 NA UGAGCCCUGUCCUCCCGCAG n.d. 1772/NA ³TOP5211 hsa-miR-1826 AUUGAUCAUCGACACUUCGAACGCAAU NA n.d. 1773/NA ⁴TOP5212 hsa-miR-383 AGAUCAGAAGGUGAUUGUGGCU NA n.d. 1774/1775 ⁴TOP5213 hsa-miR-500 UAAUCCUUGCUACCUGGGUGAGA AUGCACCUGGGCAAGGAUUCUG n.d. 1776/NA ⁴TOP5214 hsa-miR-596 AAGCCUGCCCGGCUCCUCGGG NA n.d. NA/1777 ⁴TOP5215 hsa-miR-622 NA ACAGUCUGCUGAGGUUGGAGC n.d. NA/1778 ⁵TOP5216 hsa-miR-147 NA GUGUGUGGAAAUGCUUCUGC n.d.

UPPER CASE LETTERS = RNA NA = Not available n.d. = not determined ¹Predicted by TargetScan (Entrez gene symbol: CSF2RB) ²Predicted by miRBase (EnsEMBL identifier: ENSG00000100368) ³Predicted by miRANDA (target mRNA: CSF2RB) ⁴Predicted by miRGen (Ensembl Gene ID: ENSG00000100368) ⁵Predicted by DIANAmicroT (Ensembl Gene ID: ENSG00000100368)

TABLE-US-00012 TABLE 8 oligo- Target Seq ID nucleotide Sequence gene number ID (5'-3') Human β- 1779 TOP057s ctggctcgaccggtggagg chain 1780 TOP062s gagaggtgaaggtgccggac 1781 TOP063s gtctccggtgaggtcccaggag Human 1782 TOP030s gtggagacagtggtcgtac CCR3 1783 TOP031s catgaaggccttggagagagg Non- 1784 TOP4005 atatccttgtcgtatccc specific

Sequence CWU 1

1

1785122DNAHomo sapiens 1gctggtgtag tcgttgtagc ag 22222DNAHomo sapiens 2gcaggtgatg tggctggtgt ag 22321DNAHomo sapiens 3ggctccagga ggtcctcatt c 21421DNAHomo sapiens 4ggctgaccag ggcatgtcat c 21521DNAHomo sapiens 5ctcaggaggc tggacatgct g 21619DNAHomo sapiens 6ggccacactc caggtcagc 19719DNAHomo sapiens 7ccacctcctt cctcacctc 19819DNAHomo sapiens 8gaccgagctg gccacctcc 19920DNAHomo sapiens 9ctgtctccat ccttggtcac 201022DNAHomo sapiens 10gtcttgctgt ccttccacgt gg 221122DNAHomo sapiens 11ctcactccac tcgctccaga tc 221221DNAHomo sapiens 12tcctctatgg tgagaggtga c 211320DNAHomo sapiens 13ctctccactt ccacggcctg 201422DNAHomo sapiens 14cagaggccac tccagggtcc tc 221520DNAHomo sapiens 15ggttcttgat ctcaggaccg 201620DNAHomo sapiens 16agccgcttgt agaccacctc 201720DNAHomo sapiens 17tggcctggga ggtgttggag 201820DNAHomo sapiens 18tcctgagagc cgagaacctg 201920DNAHomo sapiens 19ctccacttgc tgggacgtcc 202020DNAHomo sapiens 20ctggagtcgt gtcaggccca 202120DNAHomo sapiens 21agagggacca gttgcacctg 202220DNAHomo sapiens 22cggccttctc tccacttcca 202320DNAHomo sapiens 23ctcagtgtcc ccagagctca 202420DNAHomo sapiens 24tccactggcc agcccaggac 202520DNAHomo sapiens 25ttggagggag ctccacatag 202620DNAHomo sapiens 26ggattgttcc ttggtgacct 202720DNAHomo sapiens 27tggtctaggt tcttgatctc 202821DNAHomo sapiens 28aagagtcctg aagccgcttg t 212920DNAHomo sapiens 29aggaggatgg ctgcgtcctc 203018DNAHomo sapiens 30gcatgaggtg ctctggcc 183118DNAHomo sapiens 31gccacgtagg tgctgctg 183219DNAHomo sapiens 32gccaggcggg tccgtactc 193318DNAHomo sapiens 33tactcgggcc acgtaggt 183418DNAHomo sapiens 34acctctgggc tccacttg 183521DNAHomo sapiens 35cctggctggg agtcccagca a 213617DNAHomo sapiens 36gggctgggcc tcatccc 173718DNAHomo sapiens 37gaagcactcc aggttctg 183820DNAHomo sapiens 38catctccctg gtcagctctg 203920DNAHomo sapiens 39ggccagcacc atctccctgg 204020DNAHomo sapiens 40gcagcccctg ggccagcacc 204120DNAHomo sapiens 41gccatggaga gcagcccctg 204220DNAHomo sapiens 42ggccagcagg gccatggaga 204320DNAHomo sapiens 43cccagcacag ggccagcagg 204420DNAHomo sapiens 44aggctgcgct cccagcacag 204520DNAHomo sapiens 45tgcccctgcc aggctgcgct 204621DNAHomo sapiens 46tggtttcttc tgcccctgcc a 214720DNAHomo sapiens 47cgttgtagca gcgcagggtc 204820DNAHomo sapiens 48cccacctgca ggtgatgtgg 204920DNAHomo sapiens 49tgggtgtctg cccacctgca 205020DNAHomo sapiens 50ctgggcatcc tgggtgtctg 205120DNAHomo sapiens 51tgacgagccg ctgggcatcc 205220DNAHomo sapiens 52agggtcacgt tgacgagccg 205320DNAHomo sapiens 53ccggcgaatg agggtcacgt 205420DNAHomo sapiens 54cctcattcac ccggcgaatg 205520DNAHomo sapiens 55ggacactggc tccaggaggt 205620DNAHomo sapiens 56tgaggtcaca ggacactggc 205720DNAHomo sapiens 57atgtcatcac tgaggtcaca 205820DNAHomo sapiens 58gggggcaggc tgaccagggc 205920DNAHomo sapiens 59cagcggggat gggggcaggc 206020DNAHomo sapiens 60cctgggcacg cagcggggat 206120DNAHomo sapiens 61tgacacatct cctgggcacg 206221DNAHomo sapiens 62tggcagggaa tgacacatct c 216320DNAHomo sapiens 63gacaaaactc tggcagggaa 206421DNAHomo sapiens 64cgtcagtgac gacaaaactc t 216520DNAHomo sapiens 65aagtagtcaa cgtcagtgac 206620DNAHomo sapiens 66ttggaatgag aagtagtcaa 206720DNAHomo sapiens 67gcctgtctgg ttggaatgag 206820DNAHomo sapiens 68gtgcccagag gcctgtctgg 206920DNAHomo sapiens 69ggtgagccgg gtgcccagag 207020DNAHomo sapiens 70tcagagtgac ggtgagccgg 207120DNAHomo sapiens 71acatgctggg tcagagtgac 207220DNAHomo sapiens 72ccctgggctc aggaggctgg 207321DNAHomo sapiens 73atctgcaggt ccctgggctc a 217420DNAHomo sapiens 74gtcggtgctg atctgcaggt 207520DNAHomo sapiens 75agtggtcctg gtcggtgctg 207620DNAHomo sapiens 76gtcagcagga agtggtcctg 207720DNAHomo sapiens 77tcccaagggc cacactccag 207822DNAHomo sapiens 78ctctggggac tcccaagggc ca 227920DNAHomo sapiens 79caaccagtgg ctctggggac 208018DNAHomo sapiens 80cctggggaca accagtgg 188120DNAHomo sapiens 81aactccagat cccctgggga 208220DNAHomo sapiens 82ccacctcaaa ctccagatcc 208320DNAHomo sapiens 83gcctcactcc actcgctcca 208420DNAHomo sapiens 84ccaggagcgc gcctcactcc 208520DNAHomo sapiens 85actcggtgtc ccaggagcgc 208620DNAHomo sapiens 86ggcagcaccg actcggtgtc 208720DNAHomo sapiens 87cacccacata ggcagcaccg 208820DNAHomo sapiens 88tgagggccag cacccacata 208920DNAHomo sapiens 89aagatcacga tgagggccag 209020DNAHomo sapiens 90gatggtgagg aagatcacga 209120DNAHomo sapiens 91ggagcacagc gatggtgagg 209220DNAHomo sapiens 92cggagggcca ggagcacagc 209320DNAHomo sapiens 93gccacagaag cggagggcca 209420DNAHomo sapiens 94acccgtagat gccacagaag 209520DNAHomo sapiens 95cgcagcctgt acccgtagat 209620DNAHomo sapiens 96ccactttctg cgcagcctgt 209720DNAHomo sapiens 97tcttctcctc ccactttctg 209820DNAHomo sapiens 98gggttgggga tcttctcctc 209920DNAHomo sapiens 99gctcttgctg gggttgggga 2010020DNAHomo sapiens 100ggaacaggtg gctcttgctg 2010120DNAHomo sapiens 101ctcccgttct ggaacaggtg 2010220DNAHomo sapiens 102aagctctgcg ctcccgttct 2010320DNAHomo sapiens 103ctgggggcca aagctctgcg 2010420DNAHomo sapiens 104gacatgctgc ctgggggcca 2010520DNAHomo sapiens 105agtgaaggcc gacatgctgc 2010620DNAHomo sapiens 106gactcccgct agtgaaggcc 2010720DNAHomo sapiens 107tggtgtgggg gactcccgct 2010820DNAHomo sapiens 108ccacggcccc tggtgtgggg 2010920DNAHomo sapiens 109agcggctgcc ccacggcccc 2011020DNAHomo sapiens 110agctcaggga agcggctgcc 2011120DNAHomo sapiens 111caccccctcc agctcaggga 2011220DNAHomo sapiens 112ctacagggaa caccccctcc 2011320DNAHomo sapiens 113tccccgaatc ctacagggaa 2011420DNAHomo sapiens 114cacctcgctg tccccgaatc 2011520DNAHomo sapiens 115tgagaggtga cacctcgctg 2011620DNAHomo sapiens 116atgcttgggg tcctctatgg 2011720DNAHomo sapiens 117gatcacagac atgcttgggg 2011820DNAHomo sapiens 118ccagatggtg gatcacagac 2011920DNAHomo sapiens 119cgtgtcaggc ccagatggtg 2012020DNAHomo sapiens 120agatctgagg cagctggagt 2012120DNAHomo sapiens 121ctctgtgggt agatctgagg 2012220DNAHomo sapiens 122tggggggctg ctctgtgggt 2012320DNAHomo sapiens 123ggctgggggc tggggggctg 2012420DNAHomo sapiens 124aggcgggcct ggctgggggc 2012520DNAHomo sapiens 125gggaggcggc aggcgggcct 2012620DNAHomo sapiens 126tcaggtgtgt gggaggcggc 2012720DNAHomo sapiens 127agcctgtttc tcaggtgtgt 2012820DNAHomo sapiens 128caaagctgga agcctgtttc 2012920DNAHomo sapiens 129ccattgaagt caaagctgga 2013020DNAHomo sapiens 130caggtagggc ccattgaagt 2013120DNAHomo sapiens 131ggggcggccc caggtagggc 2013220DNAHomo sapiens 132gagcggctgt ggggcggccc 2013320DNAHomo sapiens 133gtcaggtagg gagcggctgt 2013420DNAHomo sapiens 134ggcccaggat gtcaggtagg 2013520DNAHomo sapiens 135ggctccggct ggcccaggat 2013620DNAHomo sapiens 136ctcctgtggg ggctccggct 2013720DNAHomo sapiens 137ggctcccacc ctcctgtggg 2013820DNAHomo sapiens 138ggggacttct ggctcccacc 2013920DNAHomo sapiens 139ccctggaggt ggggacttct 2014020DNAHomo sapiens 140actccaggga ccctggaggt 2014120DNAHomo sapiens 141agacacaggt actccaggga 2014220DNAHomo sapiens 142cccagcaggc agacacaggt 2014320DNAHomo sapiens 143gcacctgccc cccagcaggc 2014420DNAHomo sapiens 144ctgggccaga gggaccagtt 2014520DNAHomo sapiens 145gtcccatcgc ctgggccaga 2014620DNAHomo sapiens 146gcctgtcccg gtcccatcgc 2014718DNAHomo sapiens 147ctggctcggc cttctctc 1814817DNAHomo sapiens 148ctgcagcccc ctggctc 1714919DNAHomo sapiens 149agggagggac tccctgcag 1915018DNAHomo sapiens 150ggactccagg gagggact 1815117DNAHomo sapiens 151gcctcccccg gactcca 1715220DNAHomo sapiens 152caggaggggc agggcctccc 2015320DNAHomo sapiens 153ggcccaagag caggaggggc 2015420DNAHomo sapiens 154tcccaccctt ggcccaagag 2015520DNAHomo sapiens 155ggtcctgtcc tcccaccctt 2015620DNAHomo sapiens 156ctgtcctttt ggtcctgtcc 2015720DNAHomo sapiens 157atagccacag ggctgtcctt 2015820DNAHomo sapiens 158ctcatgggta tagccacagg 2015920DNAHomo sapiens 159tccccagagc tcatgggtat 2016019DNAHomo sapiens 160cataaccaga ggccactcc 1916120DNAHomo sapiens 161ggagacataa ccagaggcca 2016217DNAHomo sapiens 162gcagaggaga cataacc 1716318DNAHomo sapiens 163ggtgaatacc aggtctgc 1816420DNAHomo sapiens 164ctgagtttgg ggtgaatacc 2016520DNAHomo sapiens 165acagacgagg cccctgagtt 2016620DNAHomo sapiens 166actagggaga cagacgaggc 2016720DNAHomo sapiens 167cagagaggga actagggaga 2016820DNAHomo sapiens 168aggggaggcc cagagaggga 2016920DNAHomo sapiens 169gtctggtctg aggggaggcc 2017020DNAHomo sapiens 170taagctgggg gtctggtctg 2017118DNAHomo sapiens 171gcccaggaca taagctgg 1817220DNAHomo sapiens 172tccagggggt ccactggcca 2017317DNAHomo sapiens 173ggcctggggc tccaggg 1717420DNAHomo sapiens 174accctgactt cacagggcct 2017519DNAHomo sapiens 175tcaaaccctg acttcacag 1917620DNAHomo sapiens 176ccacatagcc ctcaaaccct 2017720DNAHomo sapiens 177gccctcaatt ggagggagct 2017819DNAHomo sapiens 178tgggggaccg gccctcaat 1917920DNAHomo sapiens 179cttggtgacc tgggggaccg 2018020DNAHomo sapiens 180ctcagggggg acaggattgt 2018120DNAHomo sapiens 181cttttggcct caggggggac 2018220DNAHomo sapiens 182aggacagggc ttttggcctc 2018318DNAHomo sapiens 183ccctgggttc aggacagg 1818420DNAHomo sapiens 184gccgggcgtt cccctgggtt 2018520DNAHomo sapiens 185ggacacatct gccgggcgtt 2018619DNAHomo sapiens 186ggatgttggg gacacatct 1918720DNAHomo sapiens 187tcgggctgtg gggatgttgg 2018819DNAHomo sapiens 188aggaggccct cgggctgtg 1918919DNAHomo sapiens 189gctgcaggac aaggaggcc

1919020DNAHomo sapiens 190tcgcccactt gctgcaggac 2019120DNAHomo sapiens 191gaagcaatag tcgcccactt 2019220DNAHomo sapiens 192ggccggggag gaagcaatag 2019320DNAHomo sapiens 193ccgggcccca ggccggggag 2019420DNAHomo sapiens 194cgagagaggg ccgggcccca 2019519DNAHomo sapiens 195tactccggag cgagagagg 1919618DNAHomo sapiens 196gaagaaggtt tactccgg 1819719DNAHomo sapiens 197ggtcccgggg aagaaggtt 1919819DNAHomo sapiens 198ggtcccgggg aagaaggtt 1919920DNAHomo sapiens 199tgacttgaaa agcctggtct 2020017DNAHomo sapiens 200gggcttcttg acttgaa 1720119DNAHomo sapiens 201gcctggcctg ggggcttct 1920221DNAHomo sapiens 202acctggggca cagcctggcc t 2120319DNAHomo sapiens 203tgacgggcac ctggggcac 1920420DNAHomo sapiens 204agagctgaat gacgggcacc 2020520DNAHomo sapiens 205ctagggcttt gaagagctga 2020619DNAHomo sapiens 206actgagacaa ctagggctt 1920720DNAHomo sapiens 207cacagacatc actgagacaa 2020820DNAHomo sapiens 208ctggaggtcc cacagacatc 2020920DNAHomo sapiens 209tctcaaggga ctggaggtcc 2021020DNAHomo sapiens 210tgacgtgggg tctcaaggga 2021119DNAHomo sapiens 211tcagggcttt gaagagctg 1921219DNAHomo sapiens 212tcctgctgct tcagggctt 1921319DNAHomo sapiens 213gacaggtagt cctgctgct 1921419DNAHomo sapiens 214agggggcaga gacaggtag 1921520DNAHomo sapiens 215ttgacctccc aagggggcag 2021620DNAHomo sapiens 216ttgacctccc aagggggcag 2021719DNAHomo sapiens 217ctgaagccgc ttgtagacc 1921819DNAHomo sapiens 218cgtcctccca agagtcctg 1921918DNAHomo sapiens 219ttggagagga ggatggct 1822018DNAHomo sapiens 220ctctggcccc agggtggc 1822120DNAHomo sapiens 221tgctgggcat gaggtgctct 2022218DNAHomo sapiens 222gccgagaacc tggggcca 1822317DNAHomo sapiens 223gtcccagcaa acctctg 1722417DNAHomo sapiens 224cctcatcccc tggctgg 1722517DNAHomo sapiens 225cctcatcccc tggctgg 1722617DNAHomo sapiens 226ccgtcaaaga agcactc 1722718DNAHomo sapiens 227gcacggcggc cccgtcaa 1822820DNAHomo sapiens 228gagcagctga gcacggcggc 2022919DNAHomo sapiens 229ctcacctccc aggagcagc 1923017DNAHomo sapiens 230aaggagaccg agctggc 1723120DNAHomo sapiens 231gaataggcca aaggagaccg 2023220DNAHomo sapiens 232ctgggcttgt agaataggcc 2023320DNAHomo sapiens 233tgcatctggg ctgggcttgt 2023419DNAHomo sapiens 234cttcctcccc tgcatctgg 1923517DNAHomo sapiens 235gggagcactc ttcctcc 1723620DNAHomo sapiens 236ctcagcactg gggagcactc 2023720DNAHomo sapiens 237cgagcccctc cctcagcact 2023820DNAHomo sapiens 238tggaggctgc cgagcccctc 2023920DNAHomo sapiens 239gtgcctggtg tggaggctgc 2024020DNAHomo sapiens 240tctggcagtg gtgcctggtg 2024120DNAHomo sapiens 241ggcacgggaa tctggcagtg 2024220DNAHomo sapiens 242cgcggggtcg ggcacgggaa 2024320DNAHomo sapiens 243ggccgtgggt cgcggggtcg 2024418DNAHomo sapiens 244acgatgtatt ggccgtgg 1824520DNAHomo sapiens 245ctgaacagag acgatgtatt 2024619DNAHomo sapiens 246cctccttggc tgaacagag 1924717DNAHomo sapiens 247ttctctgccc tccttgg 1724820DNAHomo sapiens 248gctctttatg tgtttctctg 2024920DNAHomo sapiens 249tgttcactga gctctttatg 2025020DNAHomo sapiens 250gccatctgga tgttcactga 2025120DNAHomo sapiens 251ggatggaggg gccatctgga 2025219DNAHomo sapiens 252tcacgttgag ggatggagg 1925321DNAHomo sapiens 253tctccatcct tggtcacgtt g 2125419DNAHomo sapiens 254gcgcaggctg tagctgtct 1925520DNAHomo sapiens 255attgtttccc agcgcaggct 2025620DNAHomo sapiens 256tcgcattttc attgtttccc 2025720DNAHomo sapiens 257tgtgttcgta tcgcattttc 2025820DNAHomo sapiens 258gtgtggtcta tgtgttcgta 2025920DNAHomo sapiens 259gatctcaaat gtgtggtcta 2026018DNAHomo sapiens 260tcctgtactg gatctcaa 1826120DNAHomo sapiens 261gccgtgtctt tcctgtactg 2026220DNAHomo sapiens 262gccgtgtctt tcctgtactg 2026318DNAHomo sapiens 263ggtctcggtc ttgctgtc 1826420DNAHomo sapiens 264ggcgttctgg agggtctcgg 2026521DNAHomo sapiens 265gccatgctgt gggcgttctg g 2126620DNAHomo sapiens 266gctggcaggg ccatgctgtg 2026718DNAHomo sapiens 267ggctccaggg ctggcagg 1826820DNAHomo sapiens 268acctggtgga gggctccagg 2026920DNAHomo sapiens 269ctggcccagt acctggtgga 2027020DNAHomo sapiens 270gaccctcacc ctggcccagt 2027120DNAHomo sapiens 271gaccctcacc ctggcccagt 2027220DNAHomo sapiens 272tagccggtgc gggaggtcct 2027320DNAHomo sapiens 273gatcccgttg tagccggtgc 2027420DNAHomo sapiens 274actcgctcca gatcccgttg 2027522DNAHomo sapiens 275tcaacacacc tccccaggct tg 2227620DNAHomo sapiens 276tgggggtctc aacacacctc 2027720DNAHomo sapiens 277tgtctaggcc tgggggtctc 2027820DNAHomo sapiens 278ttcttctgga gcctctaggc 2027920DNAHomo sapiens 279agaccagtct tcttctggag 2028020DNAHomo sapiens 280gtggtgggag agaccagtct 2028120DNAHomo sapiens 281aggcctctgt gtggtgggag 2028220DNAHomo sapiens 282tgcctcctcc aggcctctgt 2028320DNAHomo sapiens 283tcctggcctc tgcctcctcc 2028420DNAHomo sapiens 284gacctctccc tcctggcctc 2028519DNAHomo sapiens 285aggctcttgg gacctctcc 1928619DNAHomo sapiens 286ccatttcaca ggctcttgg 1928721DNAHomo sapiens 287gccaggccag acccatttca c 2128820DNAHomo sapiens 288cagctgggag ccaggccaga 2028920DNAHomo sapiens 289tgttcctgcc cagctgggag 2029020DNAHomo sapiens 290tgaagtcctg tgttcctgcc 2029120DNAHomo sapiens 291cttagtgtcc tgaagtcctg 2029220DNAHomo sapiens 292tgacagggtc cttagtgtcc 2029320DNAHomo sapiens 293gccatgggca tgacagggtc 2029420DNAHomo sapiens 294gtgggtgctg gccatgggca 2029520DNAHomo sapiens 295accagcactg gtgggtgctg 2029620DNAHomo sapiens 296acaggcaggc accagcactg 2029720DNAHomo sapiens 297tcagctctgg acaggcaggc 2029820DNAHomo sapiens 298atacctctgt gtggtgggag 2029919DNAHomo sapiens 299ggccatacct ctgtgtggt 1930021DNAHomo sapiens 300ctggacgccg ggccatacct c 2130120DNAHomo sapiens 301ggcctgcaga aggagatgtc 2030220DNAHomo sapiens 302tcctccaggc ctgcagaagg 2030320DNAHomo sapiens 303ctctgcctcc tccaggcctg 2030420DNAHomo sapiens 304caccttctgc ccctgccagg 2030521DNAHomo sapiens 305ccacgggact caccttctgc c 2130620DNAHomo sapiens 306ggagccacgg gactcacctt 2030719DNAHomo sapiens 307ttctgacaag aggggtaga 1930819DNAHomo sapiens 308ggatggtttc tgacaagag 1930920DNAHomo sapiens 309ctgcagcggg atggtttctg 2031017DNAHomo sapiens 310cactcattca cccggcg 1731120DNAHomo sapiens 311gcatcactca ctcattcacc 2031217DNAHomo sapiens 312ccagcatcac tcactca 1731320DNAHomo sapiens 313tccctgttgg gagaggacac 2031420DNAHomo sapiens 314caggaggtcc ctgttgggag 2031520DNAHomo sapiens 315ctggctccag gaggtccctg 2031620DNAHomo sapiens 316caccatgctg ggtcagagtg 2031717DNAHomo sapiens 317cctcaccatg ctgggtc 1731817DNAHomo sapiens 318ccccagcccc tcaccat 1731920DNAHomo sapiens 319ggactggagg ggaggaagtg 2032017DNAHomo sapiens 320ggaggctgga ctggagg 1732119DNAHomo sapiens 321ggctcaggag gctggactg 1932218DNAHomo sapiens 322tacctcccaa gagtcctg 1832320DNAHomo sapiens 323cgtggttcct acctcccaag 2032420DNAHomo sapiens 324ctggccgtgg ttcctacctc 2032520DNAHomo sapiens 325gtcctgtcag gagacagtgg 2032620DNAHomo sapiens 326tggctgcgtc ctgtcaggag 2032719DNAHomo sapiens 327caggacgcag ccatcctcc 1932817DNAHomo sapiens 328tacctggctg ggagtcc 1732920DNAHomo sapiens 329tggcaacatt acctggctgg 2033020DNAHomo sapiens 330ggctctggca acattacctg 2033120DNAHomo sapiens 331cccctgggtt ggagacaggt 2033220DNAHomo sapiens 332gcctcatccc ctgggttgga 2033319DNAHomo sapiens 333ggctgggcct catcccctg 1933419DNAHomo sapiens 334caccctgcat ctgggctgg 1933519DNAHomo sapiens 335gatgctcacc ctgcatctg 1933617DNAHomo sapiens 336aaaaagatgc tcaccct 1733719DNAHomo sapiens 337tccctgagga gcacagcag 1933819DNAHomo sapiens 338ctcttcctcc ctgaggagc 1933919DNAHomo sapiens 339ggagcactct tcctccctg 1934019DNAHomo sapiens 340cactgttcac tgagctctt 1934118DNAHomo sapiens 341aactcactgt tcactgag 1834220DNAHomo sapiens 342gctaggagca aactcactgt 2034320DNAHomo sapiens 343ggactggagg gagggaagct 2034420DNAHomo sapiens 344gccatctgga ctggagggag 2034520DNAHomo sapiens 345tggaggggcc atctggactg 2034620DNAHomo sapiens 346caccttccac gtggccgtgt 2034717DNAHomo sapiens 347cctcaccttc cacgtgg 1734818DNAHomo sapiens 348ggcaaaggcc ctcacctt 1834920DNAHomo sapiens 349gtcctgtggg ttggcactga 2035020DNAHomo sapiens 350tcttgctgtc ctgtgggttg 2035120DNAHomo sapiens 351gtctcggtct tgctgtcctg 2035217DNAHomo sapiens 352tacccgactc ggtgtcc 1735320DNAHomo sapiens 353gccttcacct acccgactcg 2035420DNAHomo sapiens 354ctccagcctt cacctacccg 2035517DNAHomo sapiens 355gcacttccag cagccgg 1735619DNAHomo sapiens 356cataggcagc acttccagc 1935717DNAHomo sapiens 357ccacataggc agcactt 1735820DNAHomo sapiens 358cacctgtacc cgtagatgcc 2035920DNAHomo sapiens 359gtcccctcac ctgtacccgt 2036020DNAHomo sapiens 360ccacagagtc ccctcacctg 2036120DNAHomo sapiens 361agcctggaag acaccacgga 2036220DNAHomo sapiens 362ttctgcgcag cctggaagac 2036319DNAHomo sapiens 363ccactttctg cgcagcctg 1936420DNAHomo sapiens 364tacctggaac aggtggctct 2036520DNAHomo sapiens 365cagttcctac ctggaacagg 2036620DNAHomo sapiens 366tcgcagccag ttcctacctg 2036719DNAHomo sapiens 367gttctgcaag agcagagac 1936820DNAHomo sapiens 368gcgctcccgt tctgcaagag 2036919DNAHomo sapiens 369gctctgcgct cccgttctg 1937017DNAHomo sapiens 370cacccctcca gctcagg 1737120DNAHomo sapiens 371gagcccactc acccctccag 2037220DNAHomo sapiens 372tccacgagcc cactcacccc 2037320DNAHomo sapiens 373accctgtggg aagaaaatgg 2037418DNAHomo sapiens 374ggaacaccct gtgggaag 1837519DNAHomo sapiens 375tcctacaggg aacaccctg 1937617DNAHomo sapiens 376gtctcaacac acctccc 1737720DNAHomo sapiens 377gcctgggggt ctcaacacac

2037820DNAHomo sapiens 378gtctaggcct gggggtctca 2037921DNAHomo sapiens 379agccctgctc ctggacgccg g 2138020DNAHomo sapiens 380ccacccctca gccctgctcc 2038120DNAHomo sapiens 381ctgctctgac cccacccctc 2038220DNAHomo sapiens 382tgcccctccc cttccacgtg 2038322DNAHomo sapiens 383gtcagcagtg agctgcccct cc 2238420DNAHomo sapiens 384aggagatgtc agcagtgagc 2038518DNAHomo sapiens 385agtgggtggg agccacgg 1838620DNAHomo sapiens 386agggacaggg aagtgggtgg 2038720DNAHomo sapiens 387gcagtgagga cagggacagg 2038820DNAHomo sapiens 388ctgcagggac ccttgtcacc 2038920DNAHomo sapiens 389ctctctttcc tgcagggacc 2039020DNAHomo sapiens 390agggggtcac ctctctttcc 2039120DNAHomo sapiens 391gaggggtaga agggggtcac 2039220DNAHomo sapiens 392gtggcccctg cccccagcat 2039320DNAHomo sapiens 393gcccctgccc gtggcccctg 2039419DNAHomo sapiens 394ggacgtcgta gcccctgcc 1939520DNAHomo sapiens 395agggtgtatg ggtatcactg 2039620DNAHomo sapiens 396ggcttagccc agggtgtatg 2039719DNAHomo sapiens 397gagaggacac ggcttagcc 1939818DNAHomo sapiens 398ccgggcaggg cccccagc 1839920DNAHomo sapiens 399ggaaaccaag ccccgggcag 2040020DNAHomo sapiens 400tgtccacaca ggaaaccaag 2040119DNAHomo sapiens 401ccgctggggg gcagtcagg 1940218DNAHomo sapiens 402aagggctgga ccgctggg 1840320DNAHomo sapiens 403aagggcacct aagggctgga 2040420DNAHomo sapiens 404ggaggaagtg aagggcacct 2040518DNAHomo sapiens 405ggcagagctg gccgtggt 1840620DNAHomo sapiens 406ccttcgggct ggggcagagc 2040720DNAHomo sapiens 407gctgcccatc ccttcgggct 2040820DNAHomo sapiens 408gtgctggagg aggggtgctg 2040920DNAHomo sapiens 409gagacagtgg gtgctggagg 2041020DNAHomo sapiens 410gcatttcctg ggctctggca 2041120DNAHomo sapiens 411ccaccacggg gcatttcctg 2041219DNAHomo sapiens 412gcctgccctc ccaccacgg 1941321DNAHomo sapiens 413tccgtcattc atccctccca t 2141420DNAHomo sapiens 414cctcatgtac tccgtcattc 2041520DNAHomo sapiens 415ggagacaggt cctcatgtac 2041620DNAHomo sapiens 416gaggggatgg agaaaaaaga 2041720DNAHomo sapiens 417aagaggaggg gaggggatgg 2041819DNAHomo sapiens 418gagcaaggcc aagaggagg 1941919DNAHomo sapiens 419ggagggagga gagcttagg 1942020DNAHomo sapiens 420agggcacacg ggagggagga 2042120DNAHomo sapiens 421agggagaggg agggcacacg 2042219DNAHomo sapiens 422agctgagggc agggagagg 1942320DNAHomo sapiens 423agcacagcag agctgagggc 2042419DNAHomo sapiens 424ccacagcggg ctaggagca 1942519DNAHomo sapiens 425cagaccatcc ccacagcgg 1942620DNAHomo sapiens 426gtgctggtcc cagaccatcc 2042720DNAHomo sapiens 427gtcatcatac ccaccctcca 2042820DNAHomo sapiens 428ttcaggagag tcatcatacc 2042920DNAHomo sapiens 429agggaagctt tcaggagagt 2043020DNAHomo sapiens 430ctcccctccc tgggcaaagg 2043118DNAHomo sapiens 431ccagtgtttc tcccctcc 1843219DNAHomo sapiens 432tcccgccctc cccagtgtt 1943320DNAHomo sapiens 433ccgtgggagc agctgcaaat 2043420DNAHomo sapiens 434tggcccggtg cccgtgggag 2043519DNAHomo sapiens 435ggtgaggcct ggcccggtg 1943620DNAHomo sapiens 436ttggcactga gggtgaggcc 2043720DNAHomo sapiens 437aagctctgga ctccagcctt 2043820DNAHomo sapiens 438tcctggccag aagctctgga 2043920DNAHomo sapiens 439tatgagctgg tcctggccag 2044020DNAHomo sapiens 440gaaatcgacc tcagggcagg 2044122DNAHomo sapiens 441atctgggcgg gaaatcgacc tc 2244220DNAHomo sapiens 442gaatgtcagc atctgggcgg 2044320DNAHomo sapiens 443ggagaaagag gaatgtcagc 2044420DNAHomo sapiens 444cagcagccgg ggagaaagag 2044520DNAHomo sapiens 445acctccagcc ccacagagtc 2044620DNAHomo sapiens 446acctccagcc ccacagagtc 2044720DNAHomo sapiens 447cctctggggt ctcggctgcc 2044820DNAHomo sapiens 448atcagagacc tcatggccag 2044920DNAHomo sapiens 449ggtgacagcc atcagagacc 2045020DNAHomo sapiens 450acaccacgga ggtgacagcc 2045120DNAHomo sapiens 451actccgcccc tcgcagccag 2045218DNAHomo sapiens 452agaagccccc actccgcc 1845320DNAHomo sapiens 453gcaggaacag agaagccccc 2045420DNAHomo sapiens 454gtgagcatca ggaggtccga 2045520DNAHomo sapiens 455atttgggccg gtgagcatca 2045620DNAHomo sapiens 456gagcagagac atttgggccg 2045720DNAHomo sapiens 457tcaggagtga tccacgagcc 2045820DNAHomo sapiens 458accccaaagg tcaggagtga 2045918DNAHomo sapiens 459ccgtatgaac cccaaagg 1846019DNAHomo sapiens 460gatccgggtc aggcacaag 1946121DNAHomo sapiens 461ctgggcagat gatccgggtc a 2146220DNAHomo sapiens 462tgggaccacc ctgggcagat 2046320DNAHomo sapiens 463gcagaagagt tgggaccacc 2046420DNAHomo sapiens 464aagaaaatgg gcagaagagt 2046518DNAHomo sapiens 465ccttgcctgt ctaggcct 1846619DNAHomo sapiens 466cctctccatc cccttgcct 1946720DNAHomo sapiens 467ggaaggcaag ccctctccat 2046820DNAHomo sapiens 468tccccttgcc tgtctaggcc 2046920DNAHomo sapiens 469gccctctcca tccccttgcc 2047019DNAHomo sapiens 470ggaaggcaag ccctctcca 1947120DNAHomo sapiens 471tcaggcggga gggaaggcaa 2047220DNAHomo sapiens 472ctgaggaagg tcaggcggga 2047320DNAHomo sapiens 473gcagaaatga ctgaggaagg 2047420DNAHomo sapiens 474ccttggcttt gcagaaatga 2047519DNAHomo sapiens 475ggaggctgcc ccttggctt 1947620DNAHomo sapiens 476taccttgaca ggaggctgcc 2047720DNAHomo sapiens 477ggcctctagc taccttgaca 2047820DNAHomo sapiens 478tcctttccca ggcctctagc 2047920DNAHomo sapiens 479caaggctatc tcctttccca 2048018DNAHomo sapiens 480ggccggagca aggctatc 1848120DNAHomo sapiens 481gaaggtcaag ggggccggag 2048220DNAHomo sapiens 482gtgatttgct gaaggtcaag 2048320DNAHomo sapiens 483agggagagaa gtgatttgct 2048420DNAHomo sapiens 484gtgtgagcgc agggagagaa 2048520DNAHomo sapiens 485gtgtgtgtct gtgtgagcgc 2048620DNAHomo sapiens 486acgtgtgtgt gtgtgtgtct 2048720DNAHomo sapiens 487gtgtgcatgt acgtgtgtgt 2048820DNAHomo sapiens 488caggaaaaat gtgtgcatgt 2048920DNAHomo sapiens 489gttaacctga caggaaaaat 2049020DNAHomo sapiens 490ctacaaataa gttaacctga 2049120DNAHomo sapiens 491aatgcagaac ctacaaataa 2049220DNAHomo sapiens 492aagttctaat aatgcagaac 2049320DNAHomo sapiens 493tatatctaga aagttctaat 2049420DNAHomo sapiens 494atggaatgag tatatctaga 2049520DNAHomo sapiens 495tgagggggag atggaatgag 2049620DNAHomo sapiens 496attaaaaaaa tgagggggag 2049721DNAHomo sapiens 497aggaaacctg attaaaaaaa t 2149820DNAHomo sapiens 498ggcaaaagca aggaaacctg 2049920DNAHomo sapiens 499gaagaaaaat ggcaaaagca 2050022DNAHomo sapiens 500gaaaaaagaa ggaagaaaaa tg 2250120DNAHomo sapiens 501taaatcagtg aaaaaagaag 2050220DNAHomo sapiens 502actctcataa taaatcagtg 2050320DNAHomo sapiens 503cctcagcccc actctcataa 2050418DNAHomo sapiens 504tcagctcaga cctcagcc 1850520DNAHomo sapiens 505ctgataaggc tcagctcaga 2050620DNAHomo sapiens 506gcatctcagt ctgataaggc 2050720DNAHomo sapiens 507acaaccagcc gcatctcagt 2050820DNAHomo sapiens 508agtcctcaac acaaccagcc 2050920DNAHomo sapiens 509agcccacaca agtcctcaac 2051018DNAHomo sapiens 510ggacaggcag cccacaca 1851120DNAHomo sapiens 511agcgactgcc ggggacaggc 2051220DNAHomo sapiens 512catgtgcatc agcgactgcc 2051320DNAHomo sapiens 513agaatcatgt catgtgcatc 2051420DNAHomo sapiens 514cacccagatg agaatcatgt 2051519DNAHomo sapiens 515ccacctctgc acccagatg 1951620DNAHomo sapiens 516cctggtgcct cccacctctg 2051720DNAHomo sapiens 517cgggtgccca cctggtgcct 2051820DNAHomo sapiens 518ctaaccccca cgggtgccca 2051920DNAHomo sapiens 519cttccaagcc ctaaccccca 2052020DNAHomo sapiens 520ctgtgccact cttccaagcc 2052120DNAHomo sapiens 521gtgcccagtc ctgtgccact 2052220DNAHomo sapiens 522ctcactgagc gtgcccagtc 2052320DNAHomo sapiens 523ttccctgagc ctcactgagc 2052420DNAHomo sapiens 524ctagtctgaa ttccctgagc 2052520DNAHomo sapiens 525acaatcgagg ctagtctgaa 2052620DNAHomo sapiens 526tctcggagtg acaatcgagg 2052720DNAHomo sapiens 527catgcccatt tctcggagtg 2052817DNAHomo sapiens 528ccaataccat gcccatt 1752920DNAHomo sapiens 529gcccccccga cccccaatac 2053019DNAHomo sapiens 530ccttgcaccg cccccccga 1953120DNAHomo sapiens 531tcatgtgcgt cccttgcacc 2053219DNAHomo sapiens 532aacagtctct catgtgcgt 1953320DNAHomo sapiens 533agaagctccc aaacagtctc 2053419DNAHomo sapiens 534agggctcccc agaagctcc 1953518DNAHomo sapiens 535gacaactagc agggctcc 1853620DNAHomo sapiens 536acatcactga gacaactagc 2053720DNAHomo sapiens 537ggtcccacag acatcactga 2053820DNAHomo sapiens 538agggactgga ggtcccacag 2053920DNAHomo sapiens 539tggggtctca agggactgga 2054020DNAHomo sapiens 540ctacatgacg tggggtctca 2054120DNAHomo sapiens 541gttaacttct ctacatgacg 2054220DNAHomo sapiens 542cacttgggcc gttaacttct 2054320DNAHomo sapiens 543gcctgcccac cacttgggcc 2054420DNAHomo sapiens 544ggtcccgcca gcctgcccac 2054520DNAHomo sapiens 545atgttcccca ggtcccgcca 2054620DNAHomo sapiens 546tcctctcctg atgttcccca 2054720DNAHomo sapiens 547ggctctggac tcctctcctg 2054820DNAHomo sapiens 548agtagacgtg ggctctggac 2054920DNAHomo sapiens 549acttttccgc agtagacgtg 2055020DNAHomo sapiens 550gtttcccctg acttttccgc 2055120DNAHomo sapiens 551ttgtttggca gtttcccctg 2055220DNAHomo sapiens 552gcattttcct ttgtttggca 2055320DNAHomo sapiens 553tgcctttggg gcattttcct 2055418DNAHomo sapiens 554aagcatatat gcctttgg 1855520DNAHomo sapiens 555caaaggccct aaagcatata 2055620DNAHomo sapiens 556ccatttggac caaaggccct 2055720DNAHomo sapiens 557ccatttggac caaaggccct 2055819DNAHomo sapiens 558tggaagagtg gccacccgg 1955920DNAHomo sapiens 559ctggtctatc tggaagagtg 2056020DNAHomo sapiens 560ggagagttgc ctggtctatc 2056120DNAHomo sapiens 561ccggtgggag ggagagttgc 2056220DNAHomo sapiens 562tcatctgtgg ccggtgggag 2056320DNAHomo sapiens 563cagcagcccc tcatctgtgg 2056418DNAHomo sapiens 564aggcatagat cagcagcc 1856520DNAHomo sapiens 565gtgcaggccc aggcatagat 2056619DNAHomo sapiens

566ataatccctg gtgcaggcc 1956720DNAHomo sapiens 567taaaagaacc ataatccctg 2056821DNAHomo sapiens 568aggcaaagat ttaaaagaac c 2156919DNAHomo sapiens 569gtatctgaaa ggcaaagat 1957019DNAHomo sapiens 570tatttttcct gtatctgaa 1957120DNAHomo sapiens 571ttaatgccat tatttttcct 2057220DNAHomo sapiens 572ttaaagcaat ttaatgccat 2057320DNAHomo sapiens 573ataatgcaaa ttaaagcaat 2057419DNAHomo sapiens 574gataactaaa ataatgcaa 1957519DNAHomo sapiens 575gtgcaaactg gataactaa 1957620DNAHomo sapiens 576ataaaaatat gtgcaaactg 2057720DNAHomo sapiens 577taagatacct ataaaaatat 2057820DNAHomo sapiens 578aatcgatgcc taagatacct 2057918DNAHomo sapiens 579aaaataccaa tcgatgcc 1858020DNAHomo sapiens 580tggcccagtt aaaaaatacc 2058120DNAHomo sapiens 581ttaatgggct tggcccagtt 2058220DNAHomo sapiens 582aagaaagacc ttaatgggct 2058320DNAHomo sapiens 583cacccaacag aagaaagacc 2058418DNAHomo sapiens 584aatgatagca cccaacag 1858520DNAHomo sapiens 585acttaatcag aaaatgatag 2058620DNAHomo sapiens 586agtcaaaaag acttaatcag 2058720DNAHomo sapiens 587gtatgtcaat agtcaaaaag 2058820DNAHomo sapiens 588gtgaaagact gtatgtcaat 2058920DNAHomo sapiens 589tccaccatct gtgaaagact 2059020DNAHomo sapiens 590ggaaaaacac tccaccatct 2059120DNAHomo sapiens 591cagatttggg ggaaaaacac 2059219DNAHomo sapiens 592agacaaacaa cagatttgg 1959320DNAHomo sapiens 593caacattata agacaaacaa 2059420DNAHomo sapiens 594acctcatata caacattata 2059520DNAHomo sapiens 595acaccataaa acctcatata 2059619DNAHomo sapiens 596tcatattcat acaccataa 1959720DNAHomo sapiens 597acagaagcat tcatattcat 2059820DNAHomo sapiens 598gtttgacatt acagaagcat 2059920DNAHomo sapiens 599ctagggatct gtttgacatt 2060020DNAHomo sapiens 600aaggagttta ctagggatct 2060118DNAHomo sapiens 601aagtgaagaa ggagttta 1860218DNAHomo sapiens 602aagtgaagaa ggagttta 1860320DNAHomo sapiens 603acctttgtaa atctgacagt 2060420DNAHomo sapiens 604caatgggagg acctttgtaa 2060520DNAHomo sapiens 605cactgctttg caatgggagg 2060620DNAHomo sapiens 606ttaggacaaa cactgctttg 2060719DNAHomo sapiens 607aatatataaa ttaggacaa 1960819DNAHomo sapiens 608ctagaaaaac aatatataa 1960920DNAHomo sapiens 609acaaaatgaa ctagaaaaac 2061020DNAHomo sapiens 610agttggaaac acaaaatgaa 2061120DNAHomo sapiens 611ttacatgaaa agttggaaac 2061219DNAHomo sapiens 612aattaaaatt ttacatgaa 1961320DNAHomo sapiens 613attcaaaaat aattaaaatt 2061420DNAHomo sapiens 614acatccacac attcaaaaat 2061520DNAHomo sapiens 615cctcagtctc acatccacac 2061620DNAHomo sapiens 616ccaaaaggca cctcagtctc 2061720DNAHomo sapiens 617aatttcagta ccaaaaggca 2061820DNAHomo sapiens 618atggaaaaag aatttcagta 2061920DNAHomo sapiens 619cttcaggtac atggaaaaag 2062018DNAHomo sapiens 620aagtaacact tcaggtac 1862120DNAHomo sapiens 621cctatatcac aaaagtaaca 2062220DNAHomo sapiens 622acaaggattt cctatatcac 2062319DNAHomo sapiens 623aagtatatat acaaggatt 1962419DNAHomo sapiens 624ggaccaataa agtatatat 1962520DNAHomo sapiens 625aggaagccta gggaccaata 2062620DNAHomo sapiens 626gtaacaaaat aggaagccta 2062720DNAHomo sapiens 627agaaagcaag gtaacaaaat 2062820DNAHomo sapiens 628gatgccatag agaaagcaag 2062920DNAHomo sapiens 629caaaatggtg gatgccatag 2063020DNAHomo sapiens 630gtagaacaat caaaatggtg 2063120DNAHomo sapiens 631tatcataaaa gtagaacaat 2063218DNAHomo sapiens 632tatgaaaaca tatcataa 1863320DNAHomo sapiens 633cttaaccact tatgaaaaca 2063420DNAHomo sapiens 634agaatacttg cttaaccact 2063518DNAHomo sapiens 635aagtaacgag aatacttg 1863620DNAHomo sapiens 636atttaagagc aaaagtaacg 2063720DNAHomo sapiens 637atgaataggg atttaagagc 2063819DNAHomo sapiens 638cattgctgta atgaatagg 1963920DNAHomo sapiens 639tgaccaccaa cattgctgta 2064020DNAHomo sapiens 640tcattttctt tgaccaccaa 2064120DNAHomo sapiens 641aagttgttta tcattttctt 2064220DNAHomo sapiens 642ttgaacattc aagttgttta 2064320DNAHomo sapiens 643ttcaggacca ttgaacattc 2064420DNAHomo sapiens 644tgttatgtat ttcaggacca 2064520DNAHomo sapiens 645actaaaatgt tgttatgtat 2064619DNAHomo sapiens 646ttacaatgta ctaaaatgt 1964720DNAHomo sapiens 647aggattctac tttacaatgt 2064820DNAHomo sapiens 648ttatgaacag aggattctac 2064920DNAHomo sapiens 649atcttgttca ttatgaacag 2065020DNAHomo sapiens 650acattggttc atcttgttca 2065119DNAHomo sapiens 651ttctaatcca cattggttc 1965220DNAHomo sapiens 652ctcggacttc tttctaatcc 2065318DNAHomo sapiens 653attaatatct cggacttc 1865420DNAHomo sapiens 654ggatattttg gaattaatat 2065520DNAHomo sapiens 655aacaatgtct ggatattttg 2065618DNAHomo sapiens 656ttccctttaa caatgtct 1865720DNAHomo sapiens 657ttattgcaat tttttccctt 2065820DNAHomo sapiens 658acaaatattt tattgcaatt 2065919DNAHomo sapiens 659ttttatgtta caaatattt 1966018DNAHomo sapiens 660gaccagttgc acctgccc 1866118DNAHomo sapiens 661ccacggcctg tcccggtc 1866217DNAHomo sapiens 662ggactccctg cagcccc 1766318DNAHomo sapiens 663aggggcaggg cctccccc 1866420DNAHomo sapiens 664gccacagggc tgtccttttg 2066521DNAHomo sapiens 665gccactccag ggtcctcagt g 2166618DNAHomo sapiens 666accaggtctg cagaggag 1866718DNAHomo sapiens 667cgaggcccct gagtttgg 1866818DNAHomo sapiens 668ccaggacata agctgggg 1866918DNAHomo sapiens 669gcctggggct ccaggggg 1867018DNAHomo sapiens 670ccacatagcc ctcaaacc 1867118DNAHomo sapiens 671ggacaggatt gttccttg 1867218DNAHomo sapiens 672cgttcccctg ggttcagg 1867320DNAHomo sapiens 673gtatctagtg aggttgtcat 2067420DNAHomo sapiens 674ggtctcaact gtatctagtg 2067522DNAHomo sapiens 675ccatcagtgc tctggtatca gc 2267619DNAHomo sapiens 676ggtacatcac caccaccac 1967722DNAHomo sapiens 677ggtcataatt cggagcctcc tg 2267819DNAHomo sapiens 678gcttacacat gccatggcc 1967918DNAHomo sapiens 679gctgctagca ctgccagg 1868022DNAHomo sapiens 680cctccagcta tatactgtat cc 2268118DNAHomo sapiens 681ggtccagatg cttgctcc 1868220DNAHomo sapiens 682gcatgaccag gtccagatgc 2068319DNAHomo sapiens 683cacctctgtc accagcatg 1968421DNAHomo sapiens 684gtacttccgg aacctctctc c 2168519DNAHomo sapiens 685ccacattgta gggtgtcca 1968620DNAHomo sapiens 686agtgggagta ggcgatcacc 2068720DNAHomo sapiens 687cgtagatcac cgggttcatg 2068819DNAHomo sapiens 688ttccagcttc tcactagga 1968920DNAHomo sapiens 689tggtcattct cagagtgtgg 2069020DNAHomo sapiens 690acagagctgg ttctttccag 2069120DNAHomo sapiens 691gaatgggatg tatctgccca 2069220DNAHomo sapiens 692ggatgtatct gcccaggtgc 2069320DNAHomo sapiens 693caagtgcctg tggaagaagt 2069420DNAHomo sapiens 694gcctgtggaa gaagtggcgc 2069520DNAHomo sapiens 695accaggtcca gatgcttgct 2069620DNAHomo sapiens 696attcaggaag agctgctagc 2069720DNAHomo sapiens 697gtcgattgtc agcaggatta 2069820DNAHomo sapiens 698atggaagggt gacgaggaag 2069921DNAHomo sapiensmisc_feature(1)..(19)RNA 699uuguagaaua ggccaaagga g 2170021DNAHomo sapiensmisc_feature(1)..(19)RNA 700cuuuuggccu auucuacaat t 2170121DNAHomo sapiensmisc_feature(1)..(19)RNA 701ugguggauca cagacaugct t 2170221DNAHomo sapiensmisc_feature(1)..(19)RNA 702gcaugucugu gauccaccat t 2170321DNAHomo sapiensmisc_feature(1)..(19)RNA 703uauagccaca gggcugucct t 2170421DNAHomo sapiensmisc_feature(1)..(19)RNA 704ggacagcccu guggcuauat t 2170523DNAHomo sapiensmisc_feature(1)..(21)RNA 705uauagccaca gggcuguccu utt 2370623DNAHomo sapiensmisc_feature(1)..(21)RNA 706aaggacagcc cuguggcuau att 2370723DNAHomo sapiensmisc_feature(1)..(21)RNA 707ucuauguguu cguaucgcau utt 2370823DNAHomo sapiensmisc_feature(1)..(21)RNA 708aaugcgauac gaacacauag att 2370923DNAHomo sapiensmisc_feature(1)..(21)RNA 709auguguuucu cugcccuccu utt 2371023DNAHomo sapiensmisc_feature(1)..(21)RNA 710aaggagggca gagaaacaca utt 2371121DNAHomo sapiensmisc_feature(1)..(19)RNA 711aguguccuga aguccugugt t 2171221DNAHomo sapiensmisc_feature(1)..(19)RNA 712cacaggacuu caggacacut t 2171321DNAHomo sapiensmisc_feature(1)..(19)RNA 713guggcuggug uagucguugt t 2171421DNAHomo sapiensmisc_feature(1)..(19)RNA 714caacgacuac accagccact t 2171521DNAHomo sapiensmisc_feature(1)..(19)RNA 715auguggcugg uguagucgut t 2171621DNAHomo sapiensmisc_feature(1)..(19)RNA 716acgacuacac cagccacaut t 2171721DNAHomo sapiensmisc_feature(1)..(19)RNA 717gauguggcug guguagucgt t 2171821DNAHomo sapiensmisc_feature(1)..(19)RNA 718cgacuacacc agccacauct t 2171921DNAHomo sapiensmisc_feature(1)..(19)RNA 719ggugaugugg cugguguagt t 2172021DNAHomo sapiensmisc_feature(1)..(19)RNA 720cuacaccagc cacaucacct t 2172121DNAHomo sapiensmisc_feature(1)..(19)RNA 721gcaggugaug uggcuggugt t 2172221DNAHomo sapiensmisc_feature(1)..(19)RNA 722caccagccac aucaccugct t 2172321DNAHomo sapiensmisc_feature(1)..(19)RNA 723cugcagguga uguggcuggt t 2172421DNAHomo sapiensmisc_feature(1)..(19)RNA 724ccagccacau caccugcagt t 2172521DNAHomo sapiensmisc_feature(1)..(19)RNA 725caccugcagg ugauguggct t 2172621DNAHomo sapiensmisc_feature(1)..(19)RNA 726gccacaucac cugcaggugt t 2172721DNAHomo sapiensmisc_feature(1)..(19)RNA 727ugcccaccug caggugaugt t 2172821DNAHomo sapiensmisc_feature(1)..(19)RNA 728caucaccugc aggugggcat t 2172921DNAHomo sapiensmisc_feature(1)..(19)RNA 729ucugcccacc ugcaggugat t 2173021DNAHomo sapiensmisc_feature(1)..(19)RNA 730ucaccugcag gugggcagat t 2173121DNAHomo sapiensmisc_feature(1)..(19)RNA 731gugucugccc accugcaggt t 2173221DNAHomo sapiensmisc_feature(1)..(19)RNA 732ccugcaggug ggcagacact t 2173321DNAHomo sapiensmisc_feature(1)..(19)RNA 733uccugggugu cugcccacct t 2173421DNAHomo sapiensmisc_feature(1)..(19)RNA 734uccugggugu cugcccacct t 2173521DNAHomo sapiensmisc_feature(1)..(19)RNA 735gcauccuggg ugucugccct t 2173621DNAHomo

sapiensmisc_feature(1)..(19)RNA 736gggcagacac ccaggaugct t 2173721DNAHomo sapiensmisc_feature(1)..(19)RNA 737gcugggcauc cuggguguct t 2173821DNAHomo sapiensmisc_feature(1)..(19)RNA 738gacacccagg augcccagct t 2173921DNAHomo sapiensmisc_feature(1)..(19)RNA 739guugacgagc cgcugggcat t 2174021DNAHomo sapiensmisc_feature(1)..(19)RNA 740ugcccagcgg cucgucaact t 2174121DNAHomo sapiensmisc_feature(1)..(19)RNA 741ggucacguug acgagccgct t 2174221DNAHomo sapiensmisc_feature(1)..(19)RNA 742gcggcucguc aacgugacct t 2174321DNAHomo sapiensmisc_feature(1)..(19)RNA 743cggcgaauga gggucacgut t 2174421DNAHomo sapiensmisc_feature(1)..(19)RNA 744acgugacccu cauucgccgt t 2174521DNAHomo sapiensmisc_feature(1)..(19)RNA 745ccggcgaaug agggucacgt t 2174621DNAHomo sapiensmisc_feature(1)..(19)RNA 746cgugacccuc auucgccggt t 2174721DNAHomo sapiensmisc_feature(1)..(19)RNA 747cgugacccuc auucgccggt t 2174821DNAHomo sapiensmisc_feature(1)..(19)RNA 748cccucauucg ccgggugaat t 2174921DNAHomo sapiensmisc_feature(1)..(19)RNA 749uucacccggc gaaugagggt t 2175021DNAHomo sapiensmisc_feature(1)..(19)RNA 750cccucauucg ccgggugaat t 2175121DNAHomo sapiensmisc_feature(1)..(19)RNA 751uccucauuca cccggcgaat t 2175221DNAHomo sapiensmisc_feature(1)..(19)RNA 752uucgccgggu gaaugaggat t 2175321DNAHomo sapiensmisc_feature(1)..(19)RNA 753ggcuccagga gguccucaut t 2175421DNAHomo sapiensmisc_feature(1)..(19)RNA 754augaggaccu ccuggagcct t 2175521DNAHomo sapiensmisc_feature(1)..(19)RNA 755uggcuccagg agguccucat t 2175621DNAHomo sapiensmisc_feature(1)..(19)RNA 756ugaggaccuc cuggagccat t 2175721DNAHomo sapiensmisc_feature(1)..(19)RNA 757cacuggcucc aggaggucct t 2175821DNAHomo sapiensmisc_feature(1)..(19)RNA 758ggaccuccug gagccagugt t 2175921DNAHomo sapiensmisc_feature(1)..(19)RNA 759cacuggcucc aggaggucct t 2176021DNAHomo sapiensmisc_feature(1)..(19)RNA 760ggaccuccug gagccagugt t 2176121DNAHomo sapiensmisc_feature(1)..(19)RNA 761ggacacuggc uccaggaggt t 2176221DNAHomo sapiensmisc_feature(1)..(19)RNA 762ccuccuggag ccagugucct t 2176321DNAHomo sapiensmisc_feature(1)..(19)RNA 763gaggucacag gacacuggct t 2176421DNAHomo sapiensmisc_feature(1)..(19)RNA 764gccagugucc ugugaccuct t 2176521DNAHomo sapiensmisc_feature(1)..(19)RNA 765cacugagguc acaggacact t 2176621DNAHomo sapiensmisc_feature(1)..(19)RNA 766guguccugug accucagugt t 2176721DNAHomo sapiensmisc_feature(1)..(19)RNA 767gggcauguca ucacugaggt t 2176821DNAHomo sapiensmisc_feature(1)..(19)RNA 768ccucagugau gacaugccct t 2176921DNAHomo sapiensmisc_feature(1)..(19)RNA 769gggcauguca ucacugaggt t 2177021DNAHomo sapiensmisc_feature(1)..(19)RNA 770ccucagugau gacaugccct t 2177121DNAHomo sapiensmisc_feature(1)..(19)RNA 771gaccagggca ugucaucact t 2177221DNAHomo sapiensmisc_feature(1)..(19)RNA 772gugaugacau gcccugguct t 2177321DNAHomo sapiensmisc_feature(1)..(19)RNA 773ggcugaccag ggcaugucat t 2177421DNAHomo sapiensmisc_feature(1)..(19)RNA 774ugacaugccc uggucagcct t 2177521DNAHomo sapiensmisc_feature(1)..(19)RNA 775gcaggcugac cagggcaugt t 2177621DNAHomo sapiensmisc_feature(1)..(19)RNA 776caugcccugg ucagccugct t 2177721DNAHomo sapiensmisc_feature(1)..(19)RNA 777aaugacacau cuccugggct t 2177821DNAHomo sapiensmisc_feature(1)..(19)RNA 778gcccaggaga ugugucauut t 2177921DNAHomo sapiensmisc_feature(1)..(19)RNA 779cagggaauga cacaucucct t 2178021DNAHomo sapiensmisc_feature(1)..(19)RNA 780ggagaugugu cauucccugt t 2178121DNAHomo sapiensmisc_feature(1)..(19)RNA 781uggcagggaa ugacacauct t 2178221DNAHomo sapiensmisc_feature(1)..(19)RNA 782gaugugucau ucccugccat t 2178321DNAHomo sapiensmisc_feature(1)..(19)RNA 783ucuggcaggg aaugacacat t 2178421DNAHomo sapiensmisc_feature(1)..(19)RNA 784ugugucauuc ccugccagat t 2178521DNAHomo sapiensmisc_feature(1)..(19)RNA 785acaaaacucu ggcagggaat t 2178621DNAHomo sapiensmisc_feature(1)..(19)RNA 786uucccugcca gaguuuugut t 2178721DNAHomo sapiensmisc_feature(1)..(19)RNA 787gucagugacg acaaaacuct t 2178821DNAHomo sapiensmisc_feature(1)..(19)RNA 788gaguuuuguc gucacugact t 2178921DNAHomo sapiensmisc_feature(1)..(19)RNA 789acgucaguga cgacaaaact t 2179021DNAHomo sapiensmisc_feature(1)..(19)RNA 790acgucaguga cgacaaaact t 2179121DNAHomo sapiensmisc_feature(1)..(19)RNA 791aaguagucaa cgucagugat t 2179221DNAHomo sapiensmisc_feature(1)..(19)RNA 792ucacugacgu ugactacuut t 2179321DNAHomo sapiensmisc_feature(1)..(19)RNA 793gagaaguagu caacgucagt t 2179421DNAHomo sapiensmisc_feature(1)..(19)RNA 794cugacguuga cuacuucuct t 2179521DNAHomo sapiensmisc_feature(1)..(19)RNA 795gaaugagaag uagucaacgt t 2179621DNAHomo sapiensmisc_feature(1)..(19)RNA 796cguugacuac uucucauuct t 2179721DNAHomo sapiensmisc_feature(1)..(19)RNA 797ugguuggaau gagaaguagt t 2179821DNAHomo sapiensmisc_feature(1)..(19)RNA 798cuacuucuca uuccaaccat t 2179921DNAHomo sapiensmisc_feature(1)..(19)RNA 799cuucucauuc caaccagact t 2180021DNAHomo sapiensmisc_feature(1)..(19)RNA 800cuucucauuc caaccagact t 2180121DNAHomo sapiensmisc_feature(1)..(19)RNA 801gaggccuguc ugguuggaat t 2180221DNAHomo sapiensmisc_feature(1)..(19)RNA 802uuccaaccag acaggccuct t 2180321DNAHomo sapiensmisc_feature(1)..(19)RNA 803gcccagaggc cugucuggut t 2180421DNAHomo sapiensmisc_feature(1)..(19)RNA 804accagacagg ccucugggct t 2180521DNAHomo sapiensmisc_feature(1)..(19)RNA 805ccagacaggc cucugggcat t 2180621DNAHomo sapiensmisc_feature(1)..(19)RNA 806ccagacaggc cucugggcat t 2180721DNAHomo sapiensmisc_feature(1)..(19)RNA 807agagugacgg ugagccgggt t 2180821DNAHomo sapiensmisc_feature(1)..(19)RNA 808cccggcucac cgucacucut t 2180921DNAHomo sapiensmisc_feature(1)..(19)RNA 809ugcuggguca gagugacggt t 2181021DNAHomo sapiensmisc_feature(1)..(19)RNA 810ccgucacucu gacccagcat t 2181121DNAHomo sapiensmisc_feature(1)..(19)RNA 811uggacaugcu gggucagagt t 2181221DNAHomo sapiensmisc_feature(1)..(19)RNA 812cucugaccca gcauguccat t 2181321DNAHomo sapiensmisc_feature(1)..(19)RNA 813ggaggcugga caugcugggt t 2181421DNAHomo sapiensmisc_feature(1)..(19)RNA 814cccagcaugu ccagccucct t 2181521DNAHomo sapiensmisc_feature(1)..(19)RNA 815cucaggaggc uggacaugct t 2181621DNAHomo sapiensmisc_feature(1)..(19)RNA 816gcauguccag ccuccugagt t 2181721DNAHomo sapiensmisc_feature(1)..(19)RNA 817gggcucagga ggcuggacat t 2181821DNAHomo sapiensmisc_feature(1)..(19)RNA 818gggcucagga ggcuggacat t 2181921DNAHomo sapiensmisc_feature(1)..(19)RNA 819gaucugcagg ucccugggct t 2182021DNAHomo sapiensmisc_feature(1)..(19)RNA 820gcccagggac cugcagauct t 2182121DNAHomo sapiensmisc_feature(1)..(19)RNA 821gugcugaucu gcagguccct t 2182221DNAHomo sapiensmisc_feature(1)..(19)RNA 822gggaccugca gaucagcact t 2182321DNAHomo sapiensmisc_feature(1)..(19)RNA 823gucggugcug aucugcaggt t 2182421DNAHomo sapiensmisc_feature(1)..(19)RNA 824ccugcagauc agcaccgact t 2182521DNAHomo sapiensmisc_feature(1)..(19)RNA 825guccuggucg gugcugauct t 2182621DNAHomo sapiensmisc_feature(1)..(19)RNA 826gaucagcacc gaccaggact t 2182721DNAHomo sapiensmisc_feature(1)..(19)RNA 827ugguccuggu cggugcugat t 2182821DNAHomo sapiensmisc_feature(1)..(19)RNA 828ucagcaccga ccaggaccat t 2182921DNAHomo sapiensmisc_feature(1)..(19)RNA 829aagugguccu ggucggugct t 2183021DNAHomo sapiensmisc_feature(1)..(19)RNA 830gcaccgacca ggaccacuut t 2183121DNAHomo sapiensmisc_feature(1)..(19)RNA 831aggaaguggu ccuggucggt t 2183221DNAHomo sapiensmisc_feature(1)..(19)RNA 832ccgaccagga ccacuuccut t 2183321DNAHomo sapiensmisc_feature(1)..(19)RNA 833cagcaggaag ugguccuggt t 2183421DNAHomo sapiensmisc_feature(1)..(19)RNA 834ccaggaccac uuccugcugt t 2183521DNAHomo sapiensmisc_feature(1)..(19)RNA 835ggucagcagg aaguggucct t 2183621DNAHomo sapiensmisc_feature(0)..(21)DNA 836ggaccacuuc cugcugacct t 2183721DNAHomo sapiensmisc_feature(1)..(19)RNA 837ccaggucagc aggaaguggt t 2183821DNAHomo sapiensmisc_feature(1)..(19)RNA 838ccacuuccug cugaccuggt t 2183921DNAHomo sapiensmisc_feature(1)..(19)RNA 839acuccagguc agcaggaagt t 2184021DNAHomo sapiensmisc_feature(1)..(19)RNA 840cuuccugcug accuggagut t 2184121DNAHomo sapiensmisc_feature(1)..(19)RNA 841ccaagggcca cacuccaggt t 2184221DNAHomo sapiensmisc_feature(1)..(19)RNA 842ccuggagugu ggcccuuggt t 2184321DNAHomo sapiensmisc_feature(1)..(19)RNA 843ggacucccaa gggccacact t 2184421DNAHomo sapiensmisc_feature(1)..(19)RNA 844guguggcccu ugggagucct t 2184521DNAHomo sapiensmisc_feature(1)..(19)RNA 845aaccaguggc ucuggggact t 2184621DNAHomo sapiensmisc_feature(1)..(19)RNA 846guccccagag ccacugguut t 2184721DNAHomo sapiensmisc_feature(1)..(19)RNA 847uggggacaac caguggcuct t 2184821DNAHomo sapiensmisc_feature(1)..(19)RNA 848gagccacugg uuguccccat t 2184921DNAHomo sapiensmisc_feature(1)..(19)RNA 849ccuggggaca accaguggct t 2185021DNAHomo sapiensmisc_feature(1)..(19)RNA 850gccacugguu guccccaggt t 2185121DNAHomo sapiensmisc_feature(1)..(19)RNA 851gaccaccuca aacuccagat t 2185221DNAHomo sapiensmisc_feature(1)..(19)RNA 852ucuggaguuu gaggugguct t 2185321DNAHomo sapiensmisc_feature(1)..(19)RNA 853uagaccaccu caaacuccat t 2185421DNAHomo sapiensmisc_feature(1)..(19)RNA 854uggaguuuga gguggucuat t 2185521DNAHomo sapiensmisc_feature(1)..(19)RNA 855cuuguagacc accucaaact t 2185621DNAHomo sapiensmisc_feature(1)..(19)RNA 856guuugaggug gucuacaagt t 2185721DNAHomo sapiensmisc_feature(1)..(19)RNA 857aagccgcuug uagaccacct t 2185821DNAHomo sapiensmisc_feature(1)..(19)RNA 858gguggucuac aagcggcuut t 2185921DNAHomo sapiensmisc_feature(1)..(19)RNA 859agaguccuga agccgcuugt t 2186021DNAHomo sapiensmisc_feature(1)..(19)RNA 860caagcggcuu caggacucut t 2186121DNAHomo sapiensmisc_feature(1)..(19)RNA 861caagaguccu gaagccgcut t

2186221DNAHomo sapiensmisc_feature(1)..(19)RNA 862agcggcuuca ggacucuugt t 2186321DNAHomo sapiensmisc_feature(1)..(19)RNA 863ccaagagucc ugaagccgct t 2186421DNAHomo sapiens 864gcggcuucag gacucuuggt t 2186521DNAHomo sapiensmisc_feature(1)..(19)RNA 865ugcguccucc caagagucct t 2186621DNAHomo sapiensmisc_feature(1)..(19)RNA 866ggacucuugg gaggacgcat t 2186721DNAHomo sapiensmisc_feature(1)..(19)RNA 867ggcugcgucc ucccaagagt t 2186821DNAHomo sapiensmisc_feature(1)..(19)RNA 868cucuugggag gacgcagcct t 2186921DNAHomo sapiensmisc_feature(1)..(19)RNA 869gaggaggaug gcugcgucct t 2187021DNAHomo sapiensmisc_feature(1)..(19)RNA 870ggacgcagcc auccuccuct t 2187121DNAHomo sapiensmisc_feature(1)..(19)RNA 871ggagaggagg auggcugcgt t 2187221DNAHomo sapiensmisc_feature(1)..(19)RNA 872cgcagccauc cuccucucct t 2187321DNAHomo sapiensmisc_feature(1)..(19)RNA 873uguuggagag gaggauggct t 2187421DNAHomo sapiensmisc_feature(1)..(19)RNA 874gccauccucc ucuccaacat t 2187521DNAHomo sapiensmisc_feature(1)..(19)RNA 875gagguguugg agaggaggat t 2187621DNAHomo sapiensmisc_feature(1)..(19)RNA 876uccuccucuc caacaccuct t 2187721DNAHomo sapiensmisc_feature(1)..(19)RNA 877aggguggccu gggaggugut t 2187821DNAHomo sapiensmisc_feature(1)..(19)RNA 878acaccuccca ggccacccut t 2187921DNAHomo sapiensmisc_feature(1)..(19)RNA 879caggguggcc ugggaggugt t 2188021DNAHomo sapiensmisc_feature(1)..(19)RNA 880caccucccag gccacccugt t 2188121DNAHomo sapiensmisc_feature(1)..(19)RNA 881ugcugggcau gaggugcuct t 2188221DNAHomo sapiensmisc_feature(1)..(19)RNA 882gagcaccuca ugcccagcat t 2188321DNAHomo sapiensmisc_feature(1)..(19)RNA 883gcugcugggc augaggugct t 2188421DNAHomo sapiensmisc_feature(1)..(19)RNA 884gcaccucaug cccagcagct t 2188521DNAHomo sapiensmisc_feature(1)..(19)RNA 885ggugcugcug ggcaugaggt t 2188621DNAHomo sapiensmisc_feature(1)..(19)RNA 886ccucaugccc agcagcacct t 2188721DNAHomo sapiensmisc_feature(1)..(19)RNA 887acguaggugc ugcugggcat t 2188821DNAHomo sapiensmisc_feature(1)..(19)RNA 888ugcccagcag caccuacgut t 2188921DNAHomo sapiensmisc_feature(1)..(19)RNA 889acucgggcca cguaggugct t 2189021DNAHomo sapiensmisc_feature(1)..(19)RNA 890gcaccuacgu ggcccgagut t 2189121DNAHomo sapiensmisc_feature(1)..(19)RNA 891acucgggcca cguaggugct t 2189221DNAHomo sapiensmisc_feature(1)..(19)RNA 892gcaccuacgu ggcccgagut t 2189321DNAHomo sapiensmisc_feature(1)..(19)RNA 893cguacucggg ccacguaggt t 2189421DNAHomo sapiensmisc_feature(1)..(19)RNA 894ccuacguggc ccgaguacgt t 2189521DNAHomo sapiensmisc_feature(1)..(19)RNA 895guccugagag ccgagaacct t 2189621DNAHomo sapiensmisc_feature(1)..(19)RNA 896gguucucggc ucucaggact t 2189721DNAHomo sapiensmisc_feature(1)..(19)RNA 897uccacuugcu gggacgucct t 2189821DNAHomo sapiensmisc_feature(1)..(19)RNA 898ggacguccca gcaaguggat t 2189921DNAHomo sapiensmisc_feature(1)..(19)RNA 899ggcuccacuu gcugggacgt t 2190021DNAHomo sapiensmisc_feature(1)..(19)RNA 900cgucccagca aguggagcct t 2190121DNAHomo sapiensmisc_feature(1)..(19)RNA 901accucugggc uccacuugct t 2190221DNAHomo sapiensmisc_feature(1)..(19)RNA 902gcaaguggag cccagaggut t 2190321DNAHomo sapiensmisc_feature(1)..(19)RNA 903caaaccucug ggcuccacut t 2190421DNAHomo sapiensmisc_feature(1)..(19)RNA 904aguggagccc agagguuugt t 2190521DNAHomo sapiensmisc_feature(1)..(19)RNA 905aaccucuggg cuccacuugt t 2190621DNAHomo sapiensmisc_feature(1)..(19)RNA 906caaguggagc ccagagguut t 2190721DNAHomo sapiensmisc_feature(1)..(19)RNA 907gcaaaccucu gggcuccact t 2190821DNAHomo sapiensmisc_feature(1)..(19)RNA 908guggagccca gagguuugct t 2190921DNAHomo sapiensmisc_feature(1)..(19)RNA 909ucccagcaaa ccucugggct t 2191021DNAHomo sapiensmisc_feature(1)..(19)RNA 910gcccagaggu uugcugggat t 2191121DNAHomo sapiensmisc_feature(1)..(19)RNA 911gggaguccca gcaaaccuct t 2191221DNAHomo sapiensmisc_feature(1)..(19)RNA 912gagguuugcu gggacuccct t 2191321DNAHomo sapiensmisc_feature(1)..(19)RNA 913cugggagucc cagcaaacct t 2191421DNAHomo sapiensmisc_feature(1)..(19)RNA 914gguuugcugg gacucccagt t 2191521DNAHomo sapiensmisc_feature(1)..(19)RNA 915guucuggggc ugggccucat t 2191621DNAHomo sapiensmisc_feature(1)..(19)RNA 916ugaggcccag ccccagaact t 2191721DNAHomo sapiensmisc_feature(1)..(19)RNA 917gcacuccagg uucuggggct t 2191821DNAHomo sapiensmisc_feature(1)..(19)RNA 918gccccagaac cuggagugct t 2191921DNAHomo sapiensmisc_feature(1)..(19)RNA 919aaagaagcac uccagguuct t 2192021DNAHomo sapiensmisc_feature(1)..(19)RNA 920gaaccuggag ugcuucuuut t 2192121DNAHomo sapiensmisc_feature(1)..(19)RNA 921ucaaagaagc acuccaggut t 2192221DNAHomo sapiensmisc_feature(1)..(19)RNA 922accuggagug cuucuuugat t 2192321DNAHomo sapiensmisc_feature(1)..(19)RNA 923gucaaagaag cacuccaggt t 2192421DNAHomo sapiensmisc_feature(1)..(19)RNA 924ccuggagugc uucuuugact t 2192521DNAHomo sapiensmisc_feature(1)..(19)RNA 925cucaccuccc aggagcagct t 2192621DNAHomo sapiensmisc_feature(1)..(19)RNA 926gcugcuccug ggaggugagt t 2192721DNAHomo sapiensmisc_feature(1)..(19)RNA 927ggccaccucc uuccucacct t 2192821DNAHomo sapiensmisc_feature(1)..(19)RNA 928ggugaggaag gagguggcct t 2192921DNAHomo sapiensmisc_feature(1)..(19)RNA 929gagcuggcca ccuccuucct t 2193021DNAHomo sapiensmisc_feature(1)..(19)RNA 930ggaaggaggu ggccagcuct t 2193121DNAHomo sapiensmisc_feature(1)..(19)RNA 931accgagcugg ccaccuccut t 2193221DNAHomo sapiensmisc_feature(1)..(19)RNA 932aggagguggc cagcucggut t 2193321DNAHomo sapiensmisc_feature(1)..(19)RNA 933gaccgagcug gccaccucct t 2193421DNAHomo sapiensmisc_feature(1)..(19)RNA 934ggagguggcc agcucgguct t 2193521DNAHomo sapiensmisc_feature(1)..(19)RNA 935ggagaccgag cuggccacct t 2193621DNAHomo sapiensmisc_feature(1)..(19)RNA 936gguggccagc ucggucucct t 2193721DNAHomo sapiensmisc_feature(1)..(19)RNA 937aggccaaagg agaccgagct t 2193821DNAHomo sapiensmisc_feature(1)..(19)RNA 938gcucggucuc cuuuggccut t 2193921DNAHomo sapiensmisc_feature(1)..(19)RNA 939cugggcuggg cuuguagaat t 2194021DNAHomo sapiensmisc_feature(1)..(19)RNA 940uucuacaagc ccagcccagt t 2194121DNAHomo sapiensmisc_feature(1)..(19)RNA 941ugcaucuggg cugggcuugt t 2194221DNAHomo sapiensmisc_feature(1)..(19)RNA 942caagcccagc ccagaugcat t 2194321DNAHomo sapiensmisc_feature(1)..(19)RNA 943cacuggggag cacucuucct t 2194421DNAHomo sapiensmisc_feature(1)..(19)RNA 944ggaagagugc uccccagugt t 2194521DNAHomo sapiensmisc_feature(1)..(19)RNA 945cagcacuggg gagcacucut t 2194621DNAHomo sapiensmisc_feature(1)..(19)RNA 946agagugcucc ccagugcugt t 2194721DNAHomo sapiensmisc_feature(1)..(19)RNA 947ucagcacugg ggagcacuct t 2194821DNAHomo sapiensmisc_feature(1)..(19)RNA 948gagugcuccc cagugcugat t 2194921DNAHomo sapiensmisc_feature(1)..(19)RNA 949ccucagcacu ggggagcact t 2195021DNAHomo sapiensmisc_feature(1)..(19)RNA 950gugcucccca gugcugaggt t 2195121DNAHomo sapiensmisc_feature(1)..(19)RNA 951uggugccugg uguggaggct t 2195221DNAHomo sapiensmisc_feature(1)..(19)RNA 952gccuccacac caggcaccat t 2195321DNAHomo sapiensmisc_feature(1)..(19)RNA 953cuggcagugg ugccuggugt t 2195421DNAHomo sapiensmisc_feature(1)..(19)RNA 954caccaggcac cacugccagt t 2195521DNAHomo sapiensmisc_feature(1)..(19)RNA 955aucuggcagu ggugccuggt t 2195621DNAHomo sapiensmisc_feature(1)..(19)RNA 956ccaggcacca cugccagaut t 2195721DNAHomo sapiensmisc_feature(1)..(19)RNA 957ggaaucuggc aguggugcct t 2195821DNAHomo sapiensmisc_feature(1)..(19)RNA 958ggcaccacug ccagauucct t 2195921DNAHomo sapiensmisc_feature(1)..(19)RNA 959cacgggaauc uggcaguggt t 2196021DNAHomo sapiensmisc_feature(1)..(19)RNA 960ccacugccag auucccgugt t 2196121DNAHomo sapiensmisc_feature(1)..(19)RNA 961gggcacggga aucuggcagt t 2196221DNAHomo sapiensmisc_feature(1)..(19)RNA 962cugccagauu cccgugccct t 2196321DNAHomo sapiensmisc_feature(1)..(19)RNA 963acgauguauu ggccgugggt t 2196421DNAHomo sapiensmisc_feature(1)..(19)RNA 964cccacggcca auacaucgut t 2196521DNAHomo sapiensmisc_feature(1)..(19)RNA 965agagacgaug uauuggccgt t 2196621DNAHomo sapiensmisc_feature(1)..(19)RNA 966cggccaauac aucgucucut t 2196721DNAHomo sapiensmisc_feature(1)..(19)RNA 967cugaacagag acgauguaut t 2196821DNAHomo sapiensmisc_feature(1)..(19)RNA 968auacaucguc ucuguucagt t 2196921DNAHomo sapiensmisc_feature(1)..(19)RNA 969gcugaacaga gacgauguat t 2197021DNAHomo sapiensmisc_feature(1)..(19)RNA 970uacaucgucu cuguucagct t 2197121DNAHomo sapiensmisc_feature(1)..(19)RNA 971uggcugaaca gagacgaugt t 2197221DNAHomo sapiensmisc_feature(1)..(19)RNA 972caucgucucu guucagccat t 2197321DNAHomo sapiensmisc_feature(1)..(19)RNA 973cuuggcugaa cagagacgat t 2197421DNAHomo sapiensmisc_feature(1)..(19)RNA 974ucgucucugu ucagccaagt t 2197521DNAHomo sapiensmisc_feature(1)..(19)RNA 975uuucucugcc cuccuuggct t 2197621DNAHomo sapiensmisc_feature(1)..(19)RNA 976gccaaggagg gcagagaaat t 2197721DNAHomo sapiensmisc_feature(1)..(19)RNA 977ucucugcccu ccuuggcugt t 2197821DNAHomo sapiensmisc_feature(1)..(19)RNA 978cagccaagga gggcagagat t 2197921DNAHomo sapiensmisc_feature(1)..(19)RNA 979uguguuucuc ugcccuccut t 2198021DNAHomo sapiensmisc_feature(1)..(19)RNA 980aggagggcag agaaacacat t 2198121DNAHomo sapiensmisc_feature(1)..(19)RNA 981uguuucucug cccuccuugt t 2198221DNAHomo sapiensmisc_feature(1)..(19)RNA 982caaggagggc agagaaacat t 2198321DNAHomo sapiensmisc_feature(1)..(19)RNA 983auguguuucu cugcccucct t 2198421DNAHomo sapiensmisc_feature(1)..(19)RNA 984ggagggcaga gaaacacaut t 2198521DNAHomo sapiensmisc_feature(1)..(19)RNA 985uuuauguguu ucucugccct t 2198621DNAHomo sapiensmisc_feature(1)..(19)RNA 986gggcagagaa acacauaaat t 2198721DNAHomo sapiensmisc_feature(1)..(19)RNA 987ucuuuaugug uuucucugct t

2198821DNAHomo sapiensmisc_feature(1)..(19)RNA 988gcagagaaac acauaaagat t 2198921DNAHomo sapiensmisc_feature(1)..(19)RNA 989agcucuuuau guguuucuct t 2199021DNAHomo sapiensmisc_feature(1)..(19)RNA 990gagaaacaca uaaagagcut t 2199121DNAHomo sapiensmisc_feature(1)..(19)RNA 991ugagcucuuu auguguuuct t 2199221DNAHomo sapiensmisc_feature(1)..(19)RNA 992gaaacacaua aagagcucat t 2199321DNAHomo sapiensmisc_feature(1)..(19)RNA 993gagcucuuua uguguuucut t 2199421DNAHomo sapiensmisc_feature(1)..(19)RNA 994agaaacacau aaagagcuct t 2199521DNAHomo sapiensmisc_feature(1)..(19)RNA 995acugagcucu uuauguguut t 2199621DNAHomo sapiensmisc_feature(1)..(19)RNA 996aacacauaaa gagcucagut t 2199721DNAHomo sapiensmisc_feature(1)..(19)RNA 997cacugagcuc uuuaugugut t 2199821DNAHomo sapiensmisc_feature(1)..(19)RNA 998acacauaaag agcucagugt t 2199921DNAHomo sapiensmisc_feature(1)..(19)RNA 999ucacugagcu cuuuaugugt t 21100021DNAHomo sapiensmisc_feature(1)..(19)RNA 1000cacauaaaga gcucagugat t 21100121DNAHomo sapiensmisc_feature(1)..(19)RNA 1001guucacugag cucuuuaugt t 21100221DNAHomo sapiensmisc_feature(1)..(19)RNA 1002cauaaagagc ucagugaact t 21100321DNAHomo sapiensmisc_feature(1)..(19)RNA 1003uucacugagc ucuuuaugut t 21100421DNAHomo sapiensmisc_feature(1)..(19)RNA 1004acauaaagag cucagugaat t 21100521DNAHomo sapiensmisc_feature(1)..(19)RNA 1005auguucacug agcucuuuat t 21100621DNAHomo sapiensmisc_feature(1)..(19)RNA 1006uaaagagcuc agugaacaut t 21100721DNAHomo sapiensmisc_feature(1)..(19)RNA 1007uguucacuga gcucuuuaut t 21100821DNAHomo sapiensmisc_feature(1)..(19)RNA 1008cgcagaaagu gggaggagat t 21100921DNAHomo sapiensmisc_feature(1)..(19)RNA 1009ggauguucac ugagcucuut t 21101021DNAHomo sapiensmisc_feature(1)..(19)RNA 1010aagagcucag ugaacaucct t 21101121DNAHomo sapiensmisc_feature(1)..(19)RNA 1011uggauguuca cugagcucut t 21101221DNAHomo sapiensmisc_feature(1)..(19)RNA 1012agagcucagu gaacauccat t 21101321DNAHomo sapiensmisc_feature(1)..(19)RNA 1013cuggauguuc acugagcuct t 21101421DNAHomo sapiensmisc_feature(1)..(19)RNA 1014gagcucagug aacauccagt t 21101521DNAHomo sapiensmisc_feature(1)..(19)RNA 1015aucuggaugu ucacugagct t 21101621DNAHomo sapiensmisc_feature(1)..(19)RNA 1016gcucagugaa cauccagaut t 21101721DNAHomo sapiensmisc_feature(1)..(19)RNA 1017gggccaucug gauguucact t 21101821DNAHomo sapiensmisc_feature(1)..(19)RNA 1018gugaacaucc agauggccct t 21101921DNAHomo sapiensmisc_feature(1)..(19)RNA 1019ggaggggcca ucuggaugut t 21102021DNAHomo sapiensmisc_feature(1)..(19)RNA 1020acauccagau ggccccucct t 21102121DNAHomo sapiensmisc_feature(1)..(19)RNA 1021uggaggggcc aucuggaugt t 21102221DNAHomo sapiensmisc_feature(1)..(19)RNA 1022cauccagaug gccccuccat t 21102321DNAHomo sapiensmisc_feature(1)..(19)RNA 1023gauggagggg ccaucuggat t 21102421DNAHomo sapiensmisc_feature(1)..(19)RNA 1024uccagauggc cccuccauct t 21102521DNAHomo sapiensmisc_feature(1)..(19)RNA 1025gagggaugga ggggccauct t 21102621DNAHomo sapiensmisc_feature(1)..(19)RNA 1026gauggccccu ccaucccuct t 21102721DNAHomo sapiensmisc_feature(1)..(19)RNA 1027uugagggaug gaggggccat t 21102821DNAHomo sapiensmisc_feature(1)..(19)RNA 1028uggccccucc aucccucaat t 21102921DNAHomo sapiensmisc_feature(1)..(19)RNA 1029ccuuggucac guugagggat t 21103021DNAHomo sapiensmisc_feature(1)..(19)RNA 1030ucccucaacg ugaccaaggt t 21103121DNAHomo sapiensmisc_feature(1)..(19)RNA 1031ucuccauccu uggucacgut t 21103221DNAHomo sapiensmisc_feature(1)..(19)RNA 1032acgugaccaa ggauggagat t 21103321DNAHomo sapiensmisc_feature(1)..(19)RNA 1033gucuccaucc uuggucacgt t 21103421DNAHomo sapiensmisc_feature(1)..(19)RNA 1034cgugaccaag gauggagact t 21103521DNAHomo sapiensmisc_feature(1)..(19)RNA 1035uagcugucuc cauccuuggt t 21103621DNAHomo sapiensmisc_feature(1)..(19)RNA 1036ccaaggaugg agacagcuat t 21103721DNAHomo sapiensmisc_feature(1)..(19)RNA 1037cuguagcugu cuccauccut t 21103821DNAHomo sapiensmisc_feature(1)..(19)RNA 1038aggauggaga cagcuacagt t 21103921DNAHomo sapiensmisc_feature(1)..(19)RNA 1039gcuguagcug ucuccaucct t 21104021DNAHomo sapiensmisc_feature(1)..(19)RNA 1040ggauggagac agcuacagct t 21104121DNAHomo sapiensmisc_feature(1)..(19)RNA 1041caggcuguag cugucuccat t 21104221DNAHomo sapiensmisc_feature(1)..(19)RNA 1042uggagacagc uacagccugt t 21104321DNAHomo sapiensmisc_feature(1)..(19)RNA 1043agcgcaggcu guagcuguct t 21104421DNAHomo sapiensmisc_feature(1)..(19)RNA 1044gacagcuaca gccugcgcut t 21104521DNAHomo sapiensmisc_feature(1)..(19)RNA 1045ccagcgcagg cuguagcugt t 21104621DNAHomo sapiensmisc_feature(1)..(19)RNA 1046cagcuacagc cugcgcuggt t 21104721DNAHomo sapiensmisc_feature(1)..(19)RNA 1047ucccagcgca ggcuguagct t 21104821DNAHomo sapiensmisc_feature(1)..(19)RNA 1048gcuacagccu gcgcugggat t 21104921DNAHomo sapiensmisc_feature(1)..(19)RNA 1049uguuucccag cgcaggcugt t 21105021DNAHomo sapiensmisc_feature(1)..(19)RNA 1050cagccugcgc ugggaaacat t 21105121DNAHomo sapiensmisc_feature(1)..(19)RNA 1051auuguuuccc agcgcaggct t 21105221DNAHomo sapiensmisc_feature(1)..(19)RNA 1052gccugcgcug ggaaacaaut t 21105321DNAHomo sapiensmisc_feature(1)..(19)RNA 1053uuucauuguu ucccagcgct t 21105421DNAHomo sapiensmisc_feature(1)..(19)RNA 1054gcgcugggaa acaaugaaat t 21105521DNAHomo sapiensmisc_feature(1)..(19)RNA 1055auuuucauug uuucccagct t 21105621DNAHomo sapiensmisc_feature(1)..(19)RNA 1056gcugggaaac aaugaaaaut t 21105721DNAHomo sapiensmisc_feature(1)..(19)RNA 1057cguaucgcau uuucauugut t 21105821DNAHomo sapiensmisc_feature(1)..(19)RNA 1058acaaugaaaa ugcgauacgt t 21105921DNAHomo sapiensmisc_feature(1)..(19)RNA 1059ucguaucgca uuuucauugt t 21106021DNAHomo sapiensmisc_feature(1)..(19)RNA 1060caaugaaaau gcgauacgat t 21106121DNAHomo sapiensmisc_feature(1)..(19)RNA 1061guucguaucg cauuuucaut t 21106221DNAHomo sapiensmisc_feature(1)..(19)RNA 1062augaaaaugc gauacgaact t 21106321DNAHomo sapiensmisc_feature(1)..(19)RNA 1063uguucguauc gcauuuucat t 21106421DNAHomo sapiensmisc_feature(1)..(19)RNA 1064ugaaaaugcg auacgaacat t 21106521DNAHomo sapiensmisc_feature(1)..(19)RNA 1065auguguucgu aucgcauuut t 21106621DNAHomo sapiensmisc_feature(1)..(19)RNA 1066aaaugcgaua cgaacacaut t 21106721DNAHomo sapiensmisc_feature(1)..(19)RNA 1067uauguguucg uaucgcauut t 21106821DNAHomo sapiensmisc_feature(1)..(19)RNA 1068aaugcgauac gaacacauat t 21106921DNAHomo sapiensmisc_feature(1)..(19)RNA 1069cuauguguuc guaucgcaut t 21107021DNAHomo sapiensmisc_feature(1)..(19)RNA 1070augcgauacg aacacauagt t 21107121DNAHomo sapiensmisc_feature(1)..(19)RNA 1071ucuauguguu cguaucgcat t 21107221DNAHomo sapiensmisc_feature(1)..(19)RNA 1072ugcgauacga acacauagat t 21107321DNAHomo sapiensmisc_feature(1)..(19)RNA 1073cucaaaugug uggucuaugt t 21107421DNAHomo sapiensmisc_feature(1)..(19)RNA 1074cauagaccac acauuugagt t 21107521DNAHomo sapiensmisc_feature(1)..(19)RNA 1075uguggucuau guguucguat t 21107621DNAHomo sapiensmisc_feature(1)..(19)RNA 1076uacgaacaca uagaccacat t 21107721DNAHomo sapiensmisc_feature(1)..(19)RNA 1077uggucuaugu guucguauct t 21107821DNAHomo sapiensmisc_feature(1)..(19)RNA 1078gauacgaaca cauagaccat t 21107921DNAHomo sapiensmisc_feature(1)..(19)RNA 1079uguguggucu auguguucgt t 21108021DNAHomo sapiensmisc_feature(1)..(19)RNA 1080cgaacacaua gaccacacat t 21108121DNAHomo sapiensmisc_feature(1)..(19)RNA 1081aaaugugugg ucuaugugut t 21108221DNAHomo sapiensmisc_feature(1)..(19)RNA 1082acacauagac cacacauuut t 21108321DNAHomo sapiensmisc_feature(1)..(19)RNA 1083caaaugugug gucuaugugt t 21108421DNAHomo sapiensmisc_feature(1)..(19)RNA 1084cacauagacc acacauuugt t 21108521DNAHomo sapiensmisc_feature(1)..(19)RNA 1085aucucaaaug uguggucuat t 21108621DNAHomo sapiensmisc_feature(1)..(19)RNA 1086uagaccacac auuugagaut t 21108721DNAHomo sapiensmisc_feature(1)..(19)RNA 1087ggaucucaaa ugugugguct t 21108821DNAHomo sapiensmisc_feature(1)..(19)RNA 1088gaccacacau uugagaucct t 21108921DNAHomo sapiensmisc_feature(1)..(19)RNA 1089cuggaucuca aauguguggt t 21109021DNAHomo sapiensmisc_feature(1)..(19)RNA 1090ccacacauuu gagauccagt t 21109121DNAHomo sapiensmisc_feature(1)..(19)RNA 1091guacuggauc ucaaaugugt t 21109221DNAHomo sapiensmisc_feature(1)..(19)RNA 1092cacauuugag auccaguact t 21109321DNAHomo sapiensmisc_feature(1)..(19)RNA 1093cuguacugga ucucaaaugt t 21109421DNAHomo sapiensmisc_feature(1)..(19)RNA 1094cauuugagau ccaguacagt t 21109521DNAHomo sapiensmisc_feature(1)..(19)RNA 1095uccuguacug gaucucaaat t 21109621DNAHomo sapiensmisc_feature(1)..(19)RNA 1096uuugagaucc aguacaggat t 21109721DNAHomo sapiensmisc_feature(1)..(19)RNA 1097gucuuuccug uacuggauct t 21109821DNAHomo sapiensmisc_feature(1)..(19)RNA 1098gauccaguac aggaaagact t 21109921DNAHomo sapiensmisc_feature(1)..(19)RNA 1099gugucuuucc uguacuggat t 21110021DNAHomo sapiensmisc_feature(1)..(19)RNA 1100uccaguacag gaaagacact t 21110121DNAHomo sapiensmisc_feature(1)..(19)RNA 1101ggccgugucu uuccuguact t 21110221DNAHomo sapiensmisc_feature(1)..(19)RNA 1102guacaggaaa gacacggcct t 21110321DNAHomo sapiensmisc_feature(1)..(19)RNA 1103cguggccgug ucuuuccugt t 21110421DNAHomo sapiensmisc_feature(1)..(19)RNA 1104caggaaagac acggccacgt t 21110521DNAHomo sapiensmisc_feature(1)..(19)RNA 1105cacguggccg ugucuuucct t 21110621DNAHomo sapiensmisc_feature(1)..(19)RNA 1106ggaaagacac ggccacgugt t 21110721DNAHomo sapiensmisc_feature(1)..(19)RNA 1107uuccacgugg ccgugucuut t 21110821DNAHomo sapiensmisc_feature(1)..(19)RNA 1108aagacacggc cacguggaat t 21110921DNAHomo sapiensmisc_feature(1)..(19)RNA 1109cuuccacgug gccgugucut t 21111021DNAHomo sapiensmisc_feature(1)..(19)RNA 1110agacacggcc acguggaagt t 21111121DNAHomo sapiensmisc_feature(1)..(19)RNA 1111ccuuccacgu ggccguguct t 21111221DNAHomo sapiensmisc_feature(1)..(19)RNA 1112gacacggcca cguggaaggt t 21111321DNAHomo

sapiensmisc_feature(1)..(19)RNA 1113guccuuccac guggccgugt t 21111421DNAHomo sapiensmisc_feature(1)..(19)RNA 1114cacggccacg uggaaggact t 21111521DNAHomo sapiensmisc_feature(1)..(19)RNA 1115cuguccuucc acguggccgt t 21111621DNAHomo sapiensmisc_feature(1)..(19)RNA 1116cggccacgug gaaggacagt t 21111721DNAHomo sapiensmisc_feature(1)..(19)RNA 1117uugcuguccu uccacguggt t 21111821DNAHomo sapiensmisc_feature(1)..(19)RNA 1118ccacguggaa ggacagcaat t 21111921DNAHomo sapiensmisc_feature(1)..(19)RNA 1119gucuugcugu ccuuccacgt t 21112021DNAHomo sapiensmisc_feature(1)..(19)RNA 1120cguggaagga cagcaagact t 21112121DNAHomo sapiensmisc_feature(1)..(19)RNA 1121ucuugcuguc cuuccacgut t 21112221DNAHomo sapiensmisc_feature(1)..(19)RNA 1122acguggaagg acagcaagat t 21112321DNAHomo sapiensmisc_feature(1)..(19)RNA 1123ucggucuugc uguccuucct t 21112421DNAHomo sapiensmisc_feature(1)..(19)RNA 1124ggaaggacag caagaccgat t 21112521DNAHomo sapiensmisc_feature(1)..(19)RNA 1125gucucggucu ugcuguccut t 21112621DNAHomo sapiensmisc_feature(1)..(19)RNA 1126aggacagcaa gaccgagact t 21112721DNAHomo sapiensmisc_feature(1)..(19)RNA 1127ggucucgguc uugcugucct t 21112821DNAHomo sapiensmisc_feature(1)..(19)RNA 1128ggacagcaag accgagacct t 21112921DNAHomo sapiensmisc_feature(1)..(19)RNA 1129ucuggcuccc acccuccugt t 21113021DNAHomo sapiensmisc_feature(1)..(19)RNA 1130caggagggug ggagccagat t 21113121DNAHomo sapiensmisc_feature(1)..(19)RNA 1131gagggucucg gucuugcugt t 21113221DNAHomo sapiensmisc_feature(1)..(19)RNA 1132cagcaagacc gagacccuct t 21113321DNAHomo sapiensmisc_feature(1)..(19)RNA 1133uggagggucu cggucuugct t 21113421DNAHomo sapiensmisc_feature(1)..(19)RNA 1134gcaagaccga gacccuccat t 21113521DNAHomo sapiensmisc_feature(1)..(19)RNA 1135uucuggaggg ucucggucut t 21113621DNAHomo sapiensmisc_feature(1)..(19)RNA 1136agaccgagac ccuccagaat t 21113721DNAHomo sapiensmisc_feature(1)..(19)RNA 1137guucuggagg gucucgguct t 21113821DNAHomo sapiensmisc_feature(1)..(19)RNA 1138gaccgagacc cuccagaact t 21113921DNAHomo sapiensmisc_feature(1)..(19)RNA 1139gcguucugga gggucucggt t 21114021DNAHomo sapiensmisc_feature(1)..(19)RNA 1140ccgagacccu ccagaacgct t 21114121DNAHomo sapiensmisc_feature(1)..(19)RNA 1141gugggcguuc uggaggguct t 21114221DNAHomo sapiensmisc_feature(1)..(19)RNA 1142gacccuccag aacgcccact t 21114321DNAHomo sapiensmisc_feature(1)..(19)RNA 1143cugugggcgu ucuggagggt t 21114421DNAHomo sapiensmisc_feature(1)..(19)RNA 1144cccuccagaa cgcccacagt t 21114521DNAHomo sapiensmisc_feature(1)..(19)RNA 1145ggccaugcug ugggcguuct t 21114621DNAHomo sapiensmisc_feature(1)..(19)RNA 1146gaacgcccac agcauggcct t 21114721DNAHomo sapiensmisc_feature(1)..(19)RNA 1147agggccaugc ugugggcgut t 21114821DNAHomo sapiensmisc_feature(1)..(19)RNA 1148acgcccacag cauggcccut t 21114921DNAHomo sapiensmisc_feature(1)..(19)RNA 1149cagggccaug cugugggcgt t 21115021DNAHomo sapiensmisc_feature(1)..(19)RNA 1150cgcccacagc auggcccugt t 21115121DNAHomo sapiensmisc_feature(1)..(19)RNA 1151cagggccaug cugugggcgt t 21115221DNAHomo sapiensmisc_feature(1)..(19)RNA 1152cgcccacagc auggcccugt t 21115321DNAHomo sapiensmisc_feature(1)..(19)RNA 1153ccaguaccug guggagggct t 21115421DNAHomo sapiensmisc_feature(1)..(19)RNA 1154gcccuccacc agguacuggt t 21115521DNAHomo sapiensmisc_feature(1)..(19)RNA 1155acccuggccc aguaccuggt t 21115621DNAHomo sapiensmisc_feature(1)..(19)RNA 1156ccagguacug ggccagggut t 21115721DNAHomo sapiensmisc_feature(1)..(19)RNA 1157cucacccugg cccaguacct t 21115821DNAHomo sapiensmisc_feature(1)..(19)RNA 1158gguacugggc cagggugagt t 21115921DNAHomo sapiensmisc_feature(1)..(19)RNA 1159gagguccuga cccucaccct t 21116021DNAHomo sapiensmisc_feature(1)..(19)RNA 1160gggugagggu caggaccuct t 21116121DNAHomo sapiensmisc_feature(1)..(19)RNA 1161uuguagccgg ugcgggaggt t 21116221DNAHomo sapiensmisc_feature(1)..(19)RNA 1162ccucccgcac cggcuacaat t 21116321DNAHomo sapiensmisc_feature(1)..(19)RNA 1163cagaucccgu uguagccggt t 21116421DNAHomo sapiensmisc_feature(1)..(19)RNA 1164ccggcuacaa cgggaucugt t 21116521DNAHomo sapiensmisc_feature(1)..(19)RNA 1165cucgcuccag aucccguugt t 21116621DNAHomo sapiensmisc_feature(1)..(19)RNA 1166caacgggauc uggagcgagt t 21116721DNAHomo sapiensmisc_feature(1)..(19)RNA 1167cacucgcucc agaucccgut t 21116821DNAHomo sapiensmisc_feature(1)..(19)RNA 1168acgggaucug gagcgagugt t 21116921DNAHomo sapiensmisc_feature(1)..(19)RNA 1169ccacucgcuc cagaucccgt t 21117021DNAHomo sapiensmisc_feature(1)..(19)RNA 1170cgggaucugg agcgaguggt t 21117121DNAHomo sapiensmisc_feature(1)..(19)RNA 1171ucacuccacu cgcuccagat t 21117221DNAHomo sapiensmisc_feature(1)..(19)RNA 1172ucuggagcga guggagugat t 21117321DNAHomo sapiensmisc_feature(1)..(19)RNA 1173aggcagcacc gacucggugt t 21117421DNAHomo sapiensmisc_feature(1)..(19)RNA 1174caccgagucg gugcugccut t 21117521DNAHomo sapiensmisc_feature(1)..(19)RNA 1175auaggcagca ccgacucggt t 21117621DNAHomo sapiensmisc_feature(1)..(19)RNA 1176ccgagucggu gcugccuaut t 21117721DNAHomo sapiensmisc_feature(1)..(19)RNA 1177ccacauaggc agcaccgact t 21117821DNAHomo sapiensmisc_feature(1)..(19)RNA 1178gucggugcug ccuauguggt t 21117921DNAHomo sapiensmisc_feature(1)..(19)RNA 1179augagggcca gcacccacat t 21118021DNAHomo sapiensmisc_feature(1)..(19)RNA 1180ugugggugcu ggcccucaut t 21118121DNAHomo sapiensmisc_feature(1)..(19)RNA 1181auggugagga agaucacgat t 21118221DNAHomo sapiensmisc_feature(1)..(19)RNA 1182ucgugaucuu ccucaccaut t 21118321DNAHomo sapiensmisc_feature(1)..(19)RNA 1183acagcgaugg ugaggaagat t 21118421DNAHomo sapiensmisc_feature(1)..(19)RNA 1184ucuuccucac caucgcugut t 21118521DNAHomo sapiensmisc_feature(1)..(19)RNA 1185gccaggagca cagcgauggt t 21118621DNAHomo sapiensmisc_feature(1)..(19)RNA 1186ccaucgcugu gcuccuggct t 21118721DNAHomo sapiensmisc_feature(1)..(19)RNA 1187agggccagga gcacagcgat t 21118821DNAHomo sapiensmisc_feature(1)..(19)RNA 1188ucgcugugcu ccuggcccut t 21118921DNAHomo sapiensmisc_feature(1)..(19)RNA 1189cgcagccugu acccguagat t 21119021DNAHomo sapiensmisc_feature(1)..(19)RNA 1190ucuacgggua caggcugcgt t 21119121DNAHomo sapiensmisc_feature(1)..(19)RNA 1191ucugcgcagc cuguacccgt t 21119221DNAHomo sapiensmisc_feature(1)..(19)RNA 1192cggguacagg cugcgcagat t 21119321DNAHomo sapiensmisc_feature(1)..(19)RNA 1193uucugcgcag ccuguaccct t 21119421DNAHomo sapiensmisc_feature(1)..(19)RNA 1194ggguacaggc ugcgcagaat t 21119521DNAHomo sapiensmisc_feature(1)..(19)RNA 1195uuucugcgca gccuguacct t 21119621DNAHomo sapiensmisc_feature(1)..(19)RNA 1196gguacaggcu gcgcagaaat t 21119721DNAHomo sapiensmisc_feature(1)..(19)RNA 1197ccacuuucug cgcagccugt t 21119821DNAHomo sapiensmisc_feature(1)..(19)RNA 1198caggcugcgc agaaaguggt t 21119921DNAHomo sapiensmisc_feature(1)..(19)RNA 1199ucccacuuuc ugcgcagcct t 21120021DNAHomo sapiensmisc_feature(1)..(19)RNA 1200ggcugcgcag aaagugggat t 21120121DNAHomo sapiensmisc_feature(1)..(19)RNA 1201ucuccuccca cuuucugcgt t 21120221DNAHomo sapiensmisc_feature(1)..(19)RNA 1202cgcagaaagu gggaggagat t 21120321DNAHomo sapiensmisc_feature(1)..(19)RNA 1203uucuccuccc acuuucugct t 21120421DNAHomo sapiensmisc_feature(1)..(19)RNA 1204gcagaaagug ggaggagaat t 21120521DNAHomo sapiensmisc_feature(1)..(19)RNA 1205aucuucuccu cccacuuuct t 21120621DNAHomo sapiensmisc_feature(1)..(19)RNA 1206gaaaguggga ggagaagaut t 21120721DNAHomo sapiensmisc_feature(1)..(19)RNA 1207ggaucuucuc cucccacuut t 21120821DNAHomo sapiensmisc_feature(1)..(19)RNA 1208aagugggagg agaagaucct t 21120921DNAHomo sapiensmisc_feature(1)..(19)RNA 1209gggaucuucu ccucccacut t 21121021DNAHomo sapiensmisc_feature(1)..(19)RNA 1210agugggagga gaagauccct t 21121121DNAHomo sapiensmisc_feature(1)..(19)RNA 1211ggggaucuuc uccucccact t 21121221DNAHomo sapiensmisc_feature(1)..(19)RNA 1212gugggaggag aagaucccct t 21121321DNAHomo sapiensmisc_feature(1)..(19)RNA 1213gggguugggg aucuucucct t 21121421DNAHomo sapiensmisc_feature(1)..(19)RNA 1214ggagaagauc cccaacccct t 21121521DNAHomo sapiensmisc_feature(1)..(19)RNA 1215gcugggguug gggaucuuct t 21121621DNAHomo sapiensmisc_feature(1)..(19)RNA 1216gaagaucccc aaccccagct t 21121721DNAHomo sapiensmisc_feature(1)..(19)RNA 1217uugcuggggu uggggaucut t 21121821DNAHomo sapiensmisc_feature(1)..(19)RNA 1218agauccccaa ccccagcaat t 21121921DNAHomo sapiensmisc_feature(1)..(19)RNA 1219cuugcugggg uuggggauct t 21122021DNAHomo sapiensmisc_feature(1)..(19)RNA 1220gauccccaac cccagcaagt t 21122121DNAHomo sapiensmisc_feature(1)..(19)RNA 1221cucuugcugg gguuggggat t 21122221DNAHomo sapiensmisc_feature(1)..(19)RNA 1222uccccaaccc cagcaagagt t 21122321DNAHomo sapiensmisc_feature(1)..(19)RNA 1223agguggcucu ugcuggggut t 21122421DNAHomo sapiensmisc_feature(1)..(19)RNA 1224accccagcaa gagccaccut t 21122521DNAHomo sapiensmisc_feature(1)..(19)RNA 1225cagguggcuc uugcuggggt t 21122621DNAHomo sapiensmisc_feature(1)..(19)RNA 1226ccccagcaag agccaccugt t 21122721DNAHomo sapiensmisc_feature(1)..(19)RNA 1227uggaacaggu ggcucuugct t 21122821DNAHomo sapiensmisc_feature(1)..(19)RNA 1228gcaagagcca ccuguuccat t 21122921DNAHomo sapiensmisc_feature(1)..(19)RNA 1229uucuggaaca gguggcucut t 21123021DNAHomo sapiensmisc_feature(1)..(19)RNA 1230agagccaccu guuccagaat t 21123121DNAHomo sapiensmisc_feature(1)..(19)RNA 1231guucuggaac agguggcuct t 21123221DNAHomo sapiensmisc_feature(1)..(19)RNA 1232gagccaccug uuccagaact t 21123321DNAHomo sapiensmisc_feature(1)..(19)RNA 1233ccguucugga acagguggct t 21123421DNAHomo sapiensmisc_feature(1)..(19)RNA 1234gccaccuguu ccagaacggt t 21123521DNAHomo sapiensmisc_feature(1)..(19)RNA 1235gcucccguuc uggaacaggt t 21123621DNAHomo sapiensmisc_feature(1)..(19)RNA 1236ccuguuccag aacgggagct t 21123721DNAHomo sapiensmisc_feature(1)..(19)RNA 1237aagcucugcg cucccguuct t 21123821DNAHomo sapiensmisc_feature(1)..(19)RNA 1238gaacgggagc gcagagcuut t

21123921DNAHomo sapiensmisc_feature(1)..(19)RNA 1239caaagcucug cgcucccgut t 21124021DNAHomo sapiensmisc_feature(1)..(19)RNA 1240acgggagcgc agagcuuugt t 21124121DNAHomo sapiensmisc_feature(1)..(19)RNA 1241ccaaagcucu gcgcucccgt t 21124221DNAHomo sapiensmisc_feature(1)..(19)RNA 1242cgggagcgca gagcuuuggt t 21124321DNAHomo sapiensmisc_feature(1)..(19)RNA 1243ugccuggggg ccaaagcuct t 21124421DNAHomo sapiensmisc_feature(1)..(19)RNA 1244gagcuuuggc ccccaggcat t 21124521DNAHomo sapiensmisc_feature(1)..(19)RNA 1245ugaaggccga caugcugcct t 21124621DNAHomo sapiensmisc_feature(1)..(19)RNA 1246ggcagcaugu cggccuucat t 21124721DNAHomo sapiensmisc_feature(1)..(19)RNA 1247cuagugaagg ccgacaugct t 21124821DNAHomo sapiensmisc_feature(1)..(19)RNA 1248gcaugucggc cuucacuagt t 21124921DNAHomo sapiensmisc_feature(1)..(19)RNA 1249ccgcuaguga aggccgacat t 21125021DNAHomo sapiensmisc_feature(1)..(19)RNA 1250ugucggccuu cacuagcggt t 21125121DNAHomo sapiensmisc_feature(1)..(19)RNA 1251ugugggggac ucccgcuagt t 21125221DNAHomo sapiensmisc_feature(1)..(19)RNA 1252cuagcgggag ucccccacat t 21125321DNAHomo sapiensmisc_feature(1)..(19)RNA 1253cuggucuagg uucuugauct t 21125421DNAHomo sapiensmisc_feature(1)..(19)RNA 1254gaucaagaac cuagaccagt t 21125521DNAHomo sapiensmisc_feature(1)..(19)RNA 1255uccagcucag ggaagcggct t 21125621DNAHomo sapiensmisc_feature(1)..(19)RNA 1256gccgcuuccc ugagcuggat t 21125721DNAHomo sapiensmisc_feature(1)..(19)RNA 1257aauccuagag ggaacaccct t 21125821DNAHomo sapiensmisc_feature(1)..(19)RNA 1258ggguguuccc uguaggauut t 21125921DNAHomo sapiensmisc_feature(1)..(19)RNA 1259gagaggugac accucgcugt t 21126021DNAHomo sapiensmisc_feature(1)..(19)RNA 1260cagcgaggug ucaccucuct t 21126121DNAHomo sapiensmisc_feature(1)..(19)RNA 1261gugagaggug acaccucgct t 21126221DNAHomo sapiensmisc_feature(1)..(19)RNA 1262gcgagguguc accucucact t 21126321DNAHomo sapiensmisc_feature(1)..(19)RNA 1263uauggugaga ggugacacct t 21126421DNAHomo sapiensmisc_feature(1)..(19)RNA 1264ggugucaccu cucaccauat t 21126521DNAHomo sapiensmisc_feature(1)..(19)RNA 1265gguccucuau ggugagaggt t 21126621DNAHomo sapiensmisc_feature(1)..(19)RNA 1266ccucucacca uagaggacct t 21126721DNAHomo sapiensmisc_feature(1)..(19)RNA 1267ugcuuggggu ccucuauggt t 21126821DNAHomo sapiensmisc_feature(1)..(19)RNA 1268ccauagagga ccccaagcat t 21126921DNAHomo sapiensmisc_feature(1)..(19)RNA 1269acaugcuugg gguccucuat t 21127021DNAHomo sapiensmisc_feature(1)..(19)RNA 1270uagaggaccc caagcaugut t 21127121DNAHomo sapiensmisc_feature(1)..(19)RNA 1271agacaugcuu gggguccuct t 21127221DNAHomo sapiensmisc_feature(1)..(19)RNA 1272gaggacccca agcaugucut t 21127321DNAHomo sapiensmisc_feature(1)..(19)RNA 1273acagacaugc uuggggucct t 21127421DNAHomo sapiensmisc_feature(1)..(19)RNA 1274ggaccccaag caugucugut t 21127521DNAHomo sapiensmisc_feature(1)..(19)RNA 1275aucacagaca ugcuuggggt t 21127621DNAHomo sapiensmisc_feature(1)..(19)RNA 1276ccccaagcau gucugugaut t 21127721DNAHomo sapiensmisc_feature(1)..(19)RNA 1277gguggaucac agacaugcut t 21127821DNAHomo sapiensmisc_feature(1)..(19)RNA 1278agcaugucug ugauccacct t 21127921DNAHomo sapiensmisc_feature(1)..(19)RNA 1279ugguggauca cagacaugct t 21128021DNAHomo sapiensmisc_feature(1)..(19)RNA 1280gcaugucugu gauccaccat t 21128121DNAHomo sapiensmisc_feature(1)..(19)RNA 1281agauggugga ucacagacat t 21128221DNAHomo sapiensmisc_feature(1)..(19)RNA 1282ugucugugau ccaccaucut t 21128321DNAHomo sapiensmisc_feature(1)..(19)RNA 1283gucaggccca gaugguggat t 21128421DNAHomo sapiensmisc_feature(1)..(19)RNA 1284uccaccaucu gggccugact t 21128521DNAHomo sapiensmisc_feature(1)..(19)RNA 1285ucgugucagg cccagauggt t 21128621DNAHomo sapiensmisc_feature(1)..(19)RNA 1286ccaucugggc cugacacgat t 21128721DNAHomo sapiensmisc_feature(1)..(19)RNA 1287gagucguguc aggcccagat t 21128821DNAHomo sapiensmisc_feature(1)..(19)RNA 1288ucugggccug acacgacuct t 21128921DNAHomo sapiensmisc_feature(1)..(19)RNA 1289ugaggcagcu ggagucgugt t 21129021DNAHomo sapiensmisc_feature(1)..(19)RNA 1290cacgacucca gcugccucat t 21129121DNAHomo sapiensmisc_feature(1)..(19)RNA 1291ucugaggcag cuggagucgt t 21129221DNAHomo sapiensmisc_feature(1)..(19)RNA 1292cgacuccagc ugccucagat t 21129321DNAHomo sapiensmisc_feature(1)..(19)RNA 1293agaucugagg cagcuggagt t 21129421DNAHomo sapiensmisc_feature(1)..(19)RNA 1294cuccagcugc cucagaucut t 21129521DNAHomo sapiensmisc_feature(1)..(19)RNA 1295uggguagauc ugaggcagct t 21129621DNAHomo sapiensmisc_feature(1)..(19)RNA 1296gcugccucag aucuacccat t 21129721DNAHomo sapiensmisc_feature(1)..(19)RNA 1297ucugugggua gaucugaggt t 21129821DNAHomo sapiensmisc_feature(1)..(19)RNA 1298ccucagaucu acccacagat t 21129921DNAHomo sapiensmisc_feature(1)..(19)RNA 1299gcugcucugu ggguagauct t 21130021DNAHomo sapiensmisc_feature(1)..(19)RNA 1300gaucuaccca cagagcagct t 21130121DNAHomo sapiensmisc_feature(1)..(19)RNA 1301gggcugcucu guggguagat t 21130221DNAHomo sapiensmisc_feature(1)..(19)RNA 1302ucuacccaca gagcagccct t 21130321DNAHomo sapiensmisc_feature(1)..(19)RNA 1303uuucucaggu gugugggagt t 21130421DNAHomo sapiensmisc_feature(1)..(19)RNA 1304cucccacaca ccugagaaat t 21130521DNAHomo sapiensmisc_feature(1)..(19)RNA 1305uguuucucag gugugugggt t 21130621DNAHomo sapiensmisc_feature(1)..(19)RNA 1306cccacacacc ugagaaacat t 21130721DNAHomo sapiensmisc_feature(1)..(19)RNA 1307agccuguuuc ucaggugugt t 21130821DNAHomo sapiensmisc_feature(1)..(19)RNA 1308cacaccugag aaacaggcut t 21130921DNAHomo sapiensmisc_feature(1)..(19)RNA 1309gaagccuguu ucucaggugt t 21131021DNAHomo sapiensmisc_feature(1)..(19)RNA 1310caccugagaa acaggcuuct t 21131121DNAHomo sapiensmisc_feature(1)..(19)RNA 1311uggaagccug uuucucaggt t 21131221DNAHomo sapiensmisc_feature(1)..(19)RNA 1312ccugagaaac aggcuuccat t 21131321DNAHomo sapiensmisc_feature(1)..(19)RNA 1313aaagcuggaa gccuguuuct t 21131421DNAHomo sapiensmisc_feature(1)..(19)RNA 1314gaaacaggcu uccagcuuut t 21131521DNAHomo sapiensmisc_feature(1)..(19)RNA 1315aagcuggaag ccuguuucut t 21131621DNAHomo sapiensmisc_feature(1)..(19)RNA 1316agaaacaggc uuccagcuut t 21131721DNAHomo sapiensmisc_feature(1)..(19)RNA 1317ucaaagcugg aagccuguut t 21131821DNAHomo sapiensmisc_feature(1)..(19)RNA 1318aacaggcuuc cagcuuugat t 21131921DNAHomo sapiensmisc_feature(1)..(19)RNA 1319gucaaagcug gaagccugut t 21132021DNAHomo sapiensmisc_feature(1)..(19)RNA 1320acaggcuucc agcuuugact t 21132121DNAHomo sapiensmisc_feature(1)..(19)RNA 1321agucaaagcu ggaagccugt t 21132221DNAHomo sapiensmisc_feature(1)..(19)RNA 1322caggcuucca gcuuugacut t 21132321DNAHomo sapiensmisc_feature(1)..(19)RNA 1323gaagucaaag cuggaagcct t 21132421DNAHomo sapiensmisc_feature(1)..(19)RNA 1324ggcuuccagc uuugacuuct t 21132521DNAHomo sapiensmisc_feature(1)..(19)RNA 1325ggcccauuga agucaaagct t 21132621DNAHomo sapiensmisc_feature(1)..(19)RNA 1326gcuuugacuu caaugggcct t 21132721DNAHomo sapiensmisc_feature(1)..(19)RNA 1327cagguagggc ccauugaagt t 21132821DNAHomo sapiensmisc_feature(1)..(19)RNA 1328cuucaauggg cccuaccugt t 21132921DNAHomo sapiensmisc_feature(1)..(19)RNA 1329gucagguagg gagcggcugt t 21133021DNAHomo sapiensmisc_feature(1)..(19)RNA 1330cagccgcucc cuaccugact t 21133121DNAHomo sapiensmisc_feature(1)..(19)RNA 1331augucaggua gggagcggct t 21133221DNAHomo sapiensmisc_feature(1)..(19)RNA 1332gccgcucccu accugacaut t 21133321DNAHomo sapiensmisc_feature(1)..(19)RNA 1333gcuggcccag gaugucaggt t 21133421DNAHomo sapiensmisc_feature(1)..(19)RNA 1334ccugacaucc ugggccagct t 21133521DNAHomo sapiensmisc_feature(1)..(19)RNA 1335ucuggcuccc acccuccugt t 21133621DNAHomo sapiensmisc_feature(1)..(19)RNA 1336caggagggug ggagccagat t 21133721DNAHomo sapiensmisc_feature(1)..(19)RNA 1337cuucuggcuc ccacccucct t 21133821DNAHomo sapiensmisc_feature(1)..(19)RNA 1338ggaggguggg agccagaagt t 21133921DNAHomo sapiensmisc_feature(1)..(19)RNA 1339ggacuucugg cucccaccct t 21134021DNAHomo sapiensmisc_feature(1)..(19)RNA 1340gggugggagc cagaagucct t 21134121DNAHomo sapiensmisc_feature(1)..(19)RNA 1341ggaggugggg acuucuggct t 21134221DNAHomo sapiensmisc_feature(1)..(19)RNA 1342gccagaaguc cccaccucct t 21134321DNAHomo sapiensmisc_feature(1)..(19)RNA 1343cccuggaggu ggggacuuct t 21134421DNAHomo sapiensmisc_feature(1)..(19)RNA 1344gaagucccca ccuccagggt t 21134521DNAHomo sapiensmisc_feature(1)..(19)RNA 1345gacccuggag guggggacut t 21134621DNAHomo sapiensmisc_feature(1)..(19)RNA 1346aguccccacc uccaggguct t 21134721DNAHomo sapiensmisc_feature(1)..(19)RNA 1347ggacccugga gguggggact t 21134821DNAHomo sapiensmisc_feature(1)..(19)RNA 1348guccccaccu ccagggucct t 21134921DNAHomo sapiensmisc_feature(1)..(19)RNA 1349acuccaggga cccuggaggt t 21135021DNAHomo sapiensmisc_feature(1)..(19)RNA 1350ccuccagggu cccuggagut t 21135121DNAHomo sapiensmisc_feature(1)..(19)RNA 1351acagguacuc cagggaccct t 21135221DNAHomo sapiensmisc_feature(1)..(19)RNA 1352gggucccugg aguaccugut t 21135321DNAHomo sapiensmisc_feature(1)..(19)RNA 1353agcaggcaga cacagguact t 21135421DNAHomo sapiensmisc_feature(1)..(19)RNA 1354guaccugugu cugccugcut t 21135521DNAHomo sapiensmisc_feature(1)..(19)RNA 1355agcaggcaga cacagguact t 21135621DNAHomo sapiensmisc_feature(1)..(19)RNA 1356guaccugugu cugccugcut t 21135721DNAHomo sapiensmisc_feature(1)..(19)RNA 1357cagagggacc aguugcacct t 21135821DNAHomo sapiensmisc_feature(1)..(19)RNA 1358ggugcaacug gucccucugt t 21135921DNAHomo sapiensmisc_feature(1)..(19)RNA 1359cugggccaga gggaccagut t 21136021DNAHomo sapiensmisc_feature(1)..(19)RNA 1360acuggucccu cuggcccagt t 21136121DNAHomo sapiensmisc_feature(1)..(19)RNA 1361ccugggccag agggaccagt t 21136221DNAHomo sapiensmisc_feature(1)..(19)RNA 1362cuggucccuc uggcccaggt t 21136321DNAHomo sapiensmisc_feature(1)..(19)RNA 1363cuguccuggu cccaucgcct t 21136421DNAHomo

sapiensmisc_feature(1)..(19)RNA 1364ggcgauggga ccaggacagt t 21136521DNAHomo sapiensmisc_feature(1)..(19)RNA 1365acggccuguc cuggucccat t 21136621DNAHomo sapiensmisc_feature(1)..(19)RNA 1366ugggaccagg acaggccgut t 21136721DNAHomo sapiensmisc_feature(1)..(19)RNA 1367cuuccacggc cuguccuggt t 21136821DNAHomo sapiensmisc_feature(1)..(19)RNA 1368ccaggacagg ccguggaagt t 21136921DNAHomo sapiensmisc_feature(1)..(19)RNA 1369ccacuuccac ggccugucct t 21137021DNAHomo sapiensmisc_feature(1)..(19)RNA 1370ggacaggccg uggaaguggt t 21137121DNAHomo sapiensmisc_feature(1)..(19)RNA 1371ucuccacuuc cacggccugt t 21137221DNAHomo sapiensmisc_feature(1)..(19)RNA 1372caggccgugg aaguggagat t 21137321DNAHomo sapiensmisc_feature(1)..(19)RNA 1373ucucuccacu uccacggcct t 21137421DNAHomo sapiensmisc_feature(1)..(19)RNA 1374ggccguggaa guggagagat t 21137521DNAHomo sapiensmisc_feature(1)..(19)RNA 1375uucucuccac uuccacggct t 21137621DNAHomo sapiensmisc_feature(1)..(19)RNA 1376gccguggaag uggagagaat t 21137721DNAHomo sapiensmisc_feature(1)..(19)RNA 1377gcucggccuu cucuccacut t 21137821DNAHomo sapiensmisc_feature(1)..(19)RNA 1378aguggagaga aggccgagct t 21137921DNAHomo sapiensmisc_feature(1)..(19)RNA 1379ggcucggccu ucucuccact t 21138021DNAHomo sapiensmisc_feature(1)..(19)RNA 1380guggagagaa ggccgagcct t 21138121DNAHomo sapiensmisc_feature(1)..(19)RNA 1381acuccaggga gggacuccct t 21138221DNAHomo sapiensmisc_feature(1)..(19)RNA 1382gggagucccu cccuggagut t 21138321DNAHomo sapiensmisc_feature(1)..(19)RNA 1383uguccuccca cccuuggcct t 21138421DNAHomo sapiensmisc_feature(1)..(19)RNA 1384ggccaagggu gggaggacat t 21138521DNAHomo sapiensmisc_feature(1)..(19)RNA 1385gguccugucc ucccacccut t 21138621DNAHomo sapiensmisc_feature(1)..(19)RNA 1386agggugggag gacaggacct t 21138721DNAHomo sapiensmisc_feature(1)..(19)RNA 1387ugguccuguc cucccaccct t 21138821DNAHomo sapiensmisc_feature(1)..(19)RNA 1388gggugggagg acaggaccat t 21138921DNAHomo sapiensmisc_feature(1)..(19)RNA 1389uguccuuuug guccugucct t 21139021DNAHomo sapiensmisc_feature(1)..(19)RNA 1390ggacaggacc aaaaggacat t 21139121DNAHomo sapiensmisc_feature(1)..(19)RNA 1391ggcuguccuu uugguccugt t 21139221DNAHomo sapiensmisc_feature(1)..(19)RNA 1392caggaccaaa aggacagcct t 21139321DNAHomo sapiensmisc_feature(1)..(19)RNA 1393agggcugucc uuuuggucct t 21139421DNAHomo sapiensmisc_feature(1)..(19)RNA 1394ggaccaaaag gacagcccut t 21139521DNAHomo sapiensmisc_feature(1)..(19)RNA 1395cacagggcug uccuuuuggt t 21139621DNAHomo sapiensmisc_feature(1)..(19)RNA 1396ccaaaaggac agcccugugt t 21139721DNAHomo sapiensmisc_feature(1)..(19)RNA 1397agccacaggg cuguccuuut t 21139821DNAHomo sapiensmisc_feature(1)..(19)RNA 1398aaaggacagc ccuguggcut t 21139921DNAHomo sapiensmisc_feature(1)..(19)RNA 1399uagccacagg gcuguccuut t 21140021DNAHomo sapiensmisc_feature(1)..(19)RNA 1400aaggacagcc cuguggcuat t 21140121DNAHomo sapiensmisc_feature(1)..(19)RNA 1401auagccacag ggcuguccut t 21140221DNAHomo sapiensmisc_feature(1)..(19)RNA 1402aggacagccc uguggcuaut t 21140321DNAHomo sapiensmisc_feature(1)..(19)RNA 1403uauagccaca gggcugucct t 21140421DNAHomo sapiensmisc_feature(1)..(19)RNA 1404ggacagcccu guggcuauat t 21140521DNAHomo sapiensmisc_feature(1)..(19)RNA 1405ggguauagcc acagggcugt t 21140621DNAHomo sapiensmisc_feature(1)..(19)RNA 1406cagcccugug gcuauaccct t 21140721DNAHomo sapiensmisc_feature(1)..(19)RNA 1407auggguauag ccacagggct t 21140821DNAHomo sapiensmisc_feature(1)..(19)RNA 1408gcccuguggc uauacccaut t 21140921DNAHomo sapiensmisc_feature(1)..(19)RNA 1409cacuccaggg uccucagugt t 21141021DNAHomo sapiensmisc_feature(1)..(19)RNA 1410cacugaggac ccuggagugt t 21141121DNAHomo sapiensmisc_feature(1)..(19)RNA 1411gccacuccag gguccucagt t 21141221DNAHomo sapiensmisc_feature(1)..(19)RNA 1412cugaggaccc uggaguggct t 21141321DNAHomo sapiensmisc_feature(1)..(19)RNA 1413agaggccacu ccagggucct t 21141421DNAHomo sapiensmisc_feature(1)..(19)RNA 1414ggacccugga guggccucut t 21141521DNAHomo sapiensmisc_feature(1)..(19)RNA 1415accagaggcc acuccagggt t 21141621DNAHomo sapiensmisc_feature(1)..(19)RNA 1416cccuggagug gccucuggut t 21141721DNAHomo sapiensmisc_feature(1)..(19)RNA 1417uaaccagagg ccacuccagt t 21141821DNAHomo sapiensmisc_feature(1)..(19)RNA 1418cuggaguggc cucugguuat t 21141921DNAHomo sapiensmisc_feature(1)..(19)RNA 1419auaaccagag gccacuccat t 21142021DNAHomo sapiensmisc_feature(1)..(19)RNA 1420uggaguggcc ucugguuaut t 21142121DNAHomo sapiensmisc_feature(1)..(19)RNA 1421agacauaacc agaggccact t 21142221DNAHomo sapiensmisc_feature(1)..(19)RNA 1422guggccucug guuaugucut t 21142321DNAHomo sapiensmisc_feature(1)..(19)RNA 1423caggucugca gaggagacat t 21142421DNAHomo sapiensmisc_feature(1)..(19)RNA 1424ugucuccucu gcagaccugt t 21142521DNAHomo sapiensmisc_feature(1)..(19)RNA 1425uuggggugaa uaccagguct t 21142621DNAHomo sapiensmisc_feature(1)..(19)RNA 1426gaccugguau ucaccccaat t 21142721DNAHomo sapiensmisc_feature(1)..(19)RNA 1427guuuggggug aauaccaggt t 21142821DNAHomo sapiensmisc_feature(1)..(19)RNA 1428ccugguauuc accccaaact t 21142921DNAHomo sapiensmisc_feature(1)..(19)RNA 1429ggaggcccag agagggaact t 21143021DNAHomo sapiensmisc_feature(1)..(19)RNA 1430guucccucuc ugggccucct t 21143121DNAHomo sapiensmisc_feature(1)..(19)RNA 1431auaagcuggg ggucugguct t 21143221DNAHomo sapiensmisc_feature(1)..(19)RNA 1432gaccagaccc ccagcuuaut t 21143321DNAHomo sapiensmisc_feature(1)..(19)RNA 1433acauaagcug ggggucuggt t 21143421DNAHomo sapiensmisc_feature(1)..(19)RNA 1434ccagaccccc agcuuaugut t 21143521DNAHomo sapiensmisc_feature(1)..(19)RNA 1435aggacauaag cuggggguct t 21143621DNAHomo sapiensmisc_feature(1)..(19)RNA 1436gacccccagc uuauguccut t 21143721DNAHomo sapiensmisc_feature(1)..(19)RNA 1437ccaggacaua agcugggggt t 21143821DNAHomo sapiensmisc_feature(1)..(19)RNA 1438cccccagcuu auguccuggt t 21143921DNAHomo sapiensmisc_feature(1)..(19)RNA 1439gccagcccag gacauaagct t 21144021DNAHomo sapiensmisc_feature(1)..(19)RNA 1440gcuuaugucc ugggcuggct t 21144121DNAHomo sapiensmisc_feature(1)..(19)RNA 1441cacuggccag cccaggacat t 21144221DNAHomo sapiensmisc_feature(1)..(19)RNA 1442uguccugggc uggccagugt t 21144321DNAHomo sapiensmisc_feature(1)..(19)RNA 1443acuucacagg gccuggggct t 21144421DNAHomo sapiensmisc_feature(1)..(19)RNA 1444gccccaggcc cugugaagut t 21144521DNAHomo sapiensmisc_feature(1)..(19)RNA 1445acccugacuu cacagggcct t 21144621DNAHomo sapiensmisc_feature(1)..(19)RNA 1446ggcccuguga agucagggut t 21144721DNAHomo sapiensmisc_feature(1)..(19)RNA 1447uagcccucaa acccugacut t 21144821DNAHomo sapiensmisc_feature(1)..(19)RNA 1448agucaggguu ugagggcuat t 21144921DNAHomo sapiensmisc_feature(1)..(19)RNA 1449auagcccuca aacccugact t 21145021DNAHomo sapiensmisc_feature(1)..(19)RNA 1450gucaggguuu gagggcuaut t 21145121DNAHomo sapiensmisc_feature(1)..(19)RNA 1451ccacauagcc cucaaaccct t 21145221DNAHomo sapiensmisc_feature(1)..(19)RNA 1452ggguuugagg gcuauguggt t 21145321DNAHomo sapiensmisc_feature(1)..(19)RNA 1453agggagcucc acauagccct t 21145421DNAHomo sapiensmisc_feature(1)..(19)RNA 1454gggcuaugug gagcucccut t 21145521DNAHomo sapiensmisc_feature(1)..(19)RNA 1455aauuggaggg agcuccacat t 21145621DNAHomo sapiensmisc_feature(1)..(19)RNA 1456uguggagcuc ccuccaauut t 21145721DNAHomo sapiensmisc_feature(1)..(19)RNA 1457gcccucaauu ggagggagct t 21145821DNAHomo sapiensmisc_feature(1)..(19)RNA 1458gcucccucca auugagggct t 21145921DNAHomo sapiensmisc_feature(1)..(19)RNA 1459ugggggaccg gcccucaaut t 21146021DNAHomo sapiensmisc_feature(1)..(19)RNA 1460auugagggcc ggucccccat t 21146121DNAHomo sapiensmisc_feature(1)..(19)RNA 1461cugggggacc ggcccucaat t 21146221DNAHomo sapiensmisc_feature(1)..(19)RNA 1462uugagggccg gucccccagt t 21146321DNAHomo sapiensmisc_feature(1)..(19)RNA 1463ggauuguucc uuggugacct t 21146421DNAHomo sapiensmisc_feature(1)..(19)RNA 1464ggucaccaag gaacaaucct t 21146521DNAHomo sapiensmisc_feature(1)..(19)RNA 1465ggacaggauu guuccuuggt t 21146621DNAHomo sapiensmisc_feature(1)..(19)RNA 1466ccaaggaaca auccugucct t 21146721DNAHomo sapiensmisc_feature(1)..(19)RNA 1467gggggacagg auuguuccut t 21146821DNAHomo sapiensmisc_feature(1)..(19)RNA 1468aggaacaauc cuguccccct t 21146921DNAHomo sapiensmisc_feature(1)..(19)RNA 1469ggggggacag gauuguucct t 21147021DNAHomo sapiensmisc_feature(1)..(19)RNA 1470ggaacaaucc ugucccccct t 21147121DNAHomo sapiensmisc_feature(1)..(19)RNA 1471ucagggggga caggauugut t 21147221DNAHomo sapiensmisc_feature(1)..(19)RNA 1472acaauccugu ccccccugat t 21147321DNAHomo sapiensmisc_feature(1)..(19)RNA 1473cucagggggg acaggauugt t 21147421DNAHomo sapiensmisc_feature(1)..(19)RNA 1474caauccuguc cccccugagt t 21147521DNAHomo sapiensmisc_feature(1)..(19)RNA 1475gccucagggg ggacaggaut t 21147621DNAHomo sapiensmisc_feature(1)..(19)RNA 1476auccuguccc cccugaggct t 21147721DNAHomo sapiensmisc_feature(1)..(19)RNA 1477ggccucaggg gggacaggat t 21147821DNAHomo sapiensmisc_feature(1)..(19)RNA 1478uccugucccc ccugaggcct t 21147921DNAHomo sapiensmisc_feature(1)..(19)RNA 1479caggacaggg cuuuuggcct t 21148021DNAHomo sapiensmisc_feature(1)..(19)RNA 1480ggccaaaagc ccuguccugt t 21148121DNAHomo sapiensmisc_feature(1)..(19)RNA 1481ggguucagga cagggcuuut t 21148221DNAHomo sapiensmisc_feature(1)..(19)RNA 1482aaagcccugu ccugaaccct t 21148321DNAHomo sapiensmisc_feature(1)..(19)RNA 1483uggguucagg acagggcuut t 21148421DNAHomo sapiensmisc_feature(1)..(19)RNA 1484aagcccuguc cugaacccat t 21148521DNAHomo sapiensmisc_feature(1)..(19)RNA 1485cuggguucag gacagggcut t 21148621DNAHomo sapiensmisc_feature(1)..(19)RNA 1486agcccugucc ugaacccagt t 21148721DNAHomo sapiensmisc_feature(1)..(19)RNA 1487ggacacaucu gccgggcgut t 21148821DNAHomo sapiensmisc_feature(1)..(19)RNA 1488acgcccggca gaugugucct t 21148921DNAHomo sapiensmisc_feature(1)..(19)RNA 1489gggacacauc ugccgggcgt t

21149021DNAHomo sapiensmisc_feature(1)..(19)RNA 1490cgcccggcag auguguccct t 21149121DNAHomo sapiensmisc_feature(1)..(19)RNA 1491gggauguugg ggacacauct t 21149221DNAHomo sapiensmisc_feature(1)..(19)RNA 1492gauguguccc caacauccct t 21149321DNAHomo sapiensmisc_feature(1)..(19)RNA 1493uggggauguu ggggacacat t 21149421DNAHomo sapiensmisc_feature(1)..(19)RNA 1494ugugucccca acauccccat t 21149521DNAHomo sapiensmisc_feature(1)..(19)RNA 1495ccucgggcug uggggaugut t 21149621DNAHomo sapiensmisc_feature(1)..(19)RNA 1496acauccccac agcccgaggt t 21149721DNAHomo sapiensmisc_feature(1)..(19)RNA 1497cccucgggcu guggggaugt t 21149820DNAHomo sapiensmisc_feature(1)..(19)RNA 1498cauccccaca gcccgaggtt 20149921DNAHomo sapiensmisc_feature(1)..(19)RNA 1499cugcaggaca aggaggccct t 21150021DNAHomo sapiensmisc_feature(1)..(19)RNA 1500gggccuccuu guccugcagt t 21150121DNAHomo sapiensmisc_feature(1)..(19)RNA 1501auagucgccc acuugcugct t 21150221DNAHomo sapiensmisc_feature(1)..(19)RNA 1502gcagcaagug ggcgacuaut t 21150321DNAHomo sapiensmisc_feature(1)..(19)RNA 1503gcaauagucg cccacuugct t 21150421DNAHomo sapiensmisc_feature(1)..(19)RNA 1504gcaagugggc gacuauugct t 21150521DNAHomo sapiensmisc_feature(1)..(19)RNA 1505gaagcaauag ucgcccacut t 21150621DNAHomo sapiensmisc_feature(1)..(19)RNA 1506agugggcgac uauugcuuct t 21150721DNAHomo sapiensmisc_feature(1)..(19)RNA 1507ggaagcaaua gucgcccact t 21150821DNAHomo sapiensmisc_feature(1)..(19)RNA 1508gugggcgacu auugcuucct t 21150921DNAHomo sapiensmisc_feature(1)..(19)RNA 1509gccggggagg aagcaauagt t 21151021DNAHomo sapiensmisc_feature(1)..(19)RNA 1510cuauugcuuc cuccccggct t 21151121DNAHomo sapiensmisc_feature(1)..(19)RNA 1511caggccgggg aggaagcaat t 21151221DNAHomo sapiensmisc_feature(1)..(19)RNA 1512uugcuuccuc cccggccugt t 21151321DNAHomo sapiensmisc_feature(1)..(19)RNA 1513cccggggaag aagguuuact t 21151421DNAHomo sapiensmisc_feature(1)..(19)RNA 1514guaaaccuuc uuccccgggt t 21151521DNAHomo sapiensmisc_feature(1)..(19)RNA 1515ggucccgggg aagaagguut t 21151621DNAHomo sapiensmisc_feature(1)..(19)RNA 1516aaccuucuuc cccgggacct t 21151721DNAHomo sapiensmisc_feature(1)..(19)RNA 1517gggucccggg gaagaaggut t 21151821DNAHomo sapiensmisc_feature(1)..(19)RNA 1518accuucuucc ccgggaccct t 21151921DNAHomo sapiensmisc_feature(1)..(19)RNA 1519cgggucccgg ggaagaaggt t 21152021DNAHomo sapiensmisc_feature(1)..(19)RNA 1520ccuucuuccc cgggacccgt t 21152121DNAHomo sapiensmisc_feature(1)..(19)RNA 1521ucuugaucuc aggaccgggt t 21152221DNAHomo sapiensmisc_feature(1)..(19)RNA 1522cccgguccug agaucaagat t 21152321DNAHomo sapiensmisc_feature(1)..(19)RNA 1523cuggucuagg uucuugauct t 21152421DNAHomo sapiensmisc_feature(1)..(19)RNA 1524gaucaagaac cuagaccagt t 21152521DNAHomo sapiensmisc_feature(1)..(19)RNA 1525gccuggucua gguucuugat t 21152621DNAHomo sapiensmisc_feature(1)..(19)RNA 1526ucaagaaccu agaccaggct t 21152721DNAHomo sapiensmisc_feature(1)..(19)RNA 1527aaagccuggu cuagguucut t 21152821DNAHomo sapiensmisc_feature(1)..(19)RNA 1528agaaccuaga ccaggcuuut t 21152921DNAHomo sapiensmisc_feature(1)..(19)RNA 1529aaaagccugg ucuagguuct t 21153021DNAHomo sapiensmisc_feature(1)..(19)RNA 1530gaaccuagac caggcuuuut t 21153121DNAHomo sapiensmisc_feature(1)..(19)RNA 1531ugaaaagccu ggucuaggut t 21153221DNAHomo sapiensmisc_feature(1)..(19)RNA 1532accuagacca ggcuuuucat t 21153321DNAHomo sapiensmisc_feature(1)..(19)RNA 1533uugaaaagcc uggucuaggt t 21153421DNAHomo sapiensmisc_feature(1)..(19)RNA 1534ccuagaccag gcuuuucaat t 21153521DNAHomo sapiensmisc_feature(1)..(19)RNA 1535ugacuugaaa agccugguct t 21153621DNAHomo sapiensmisc_feature(1)..(19)RNA 1536gaccaggcuu uucaagucat t 21153721DNAHomo sapiensmisc_feature(1)..(19)RNA 1537cuugacuuga aaagccuggt t 21153821DNAHomo sapiensmisc_feature(1)..(19)RNA 1538ccaggcuuuu caagucaagt t 21153921DNAHomo sapiensmisc_feature(1)..(19)RNA 1539cuucuugacu ugaaaagcct t 21154021DNAHomo sapiensmisc_feature(1)..(19)RNA 1540ggcuuuucaa gucaagaagt t 21154121DNAHomo sapiensmisc_feature(1)..(19)RNA 1541gccugggggc uucuugacut t 21154221DNAHomo sapiensmisc_feature(1)..(19)RNA 1542agucaagaag cccccaggct t 21154321DNAHomo sapiensmisc_feature(1)..(19)RNA 1543ggccuggggg cuucuugact t 21154421DNAHomo sapiensmisc_feature(1)..(19)RNA 1544gucaagaagc ccccaggcct t 21154521DNAHomo sapiensmisc_feature(1)..(19)RNA 1545agccuggccu gggggcuuct t 21154621DNAHomo sapiensmisc_feature(1)..(19)RNA 1546gaagccccca ggccaggcut t 21154721DNAHomo sapiensmisc_feature(1)..(19)RNA 1547gagcugaaug acgggcacct t 21154821DNAHomo sapiensmisc_feature(1)..(19)RNA 1548ggugcccguc auucagcuct t 21154921DNAHomo sapiensmisc_feature(1)..(19)RNA 1549uugaagagcu gaaugacggt t 21155021DNAHomo sapiensmisc_feature(1)..(19)RNA 1550ccgucauuca gcucuucaat t 21155121DNAHomo sapiensmisc_feature(1)..(19)RNA 1551agggcuuuga agagcugaat t 21155221DNAHomo sapiensmisc_feature(1)..(19)RNA 1552uucagcucuu caaagcccut t 21155321DNAHomo sapiensmisc_feature(1)..(19)RNA 1553cuucagggcu uugaagagct t 21155421DNAHomo sapiensmisc_feature(1)..(19)RNA 1554gcucuucaaa gcccugaagt t 21155521DNAHomo sapiensmisc_feature(1)..(19)RNA 1555uccugcugcu ucagggcuut t 21155621DNAHomo sapiensmisc_feature(1)..(19)RNA 1556aagcccugaa gcagcaggat t 21155721DNAHomo sapiensmisc_feature(1)..(19)RNA 1557guccugcugc uucagggcut t 21155821DNAHomo sapiensmisc_feature(1)..(19)RNA 1558agcccugaag cagcaggact t 21155921DNAHomo sapiensmisc_feature(1)..(19)RNA 1559aguccugcug cuucagggct t 21156021DNAHomo sapiensmisc_feature(1)..(19)RNA 1560gcccugaagc agcaggacut t 21156121DNAHomo sapiensmisc_feature(1)..(19)RNA 1561gacagguagu ccugcugcut t 21156221DNAHomo sapiensmisc_feature(1)..(19)RNA 1562agcagcagga cuaccuguct t 21156321DNAHomo sapiensmisc_feature(1)..(19)RNA 1563agacagguag uccugcugct t 21156421DNAHomo sapiensmisc_feature(1)..(19)RNA 1564gcagcaggac uaccugucut t 21156521DNAHomo sapiensmisc_feature(1)..(19)RNA 1565cagagacagg uaguccugct t 21156621DNAHomo sapiensmisc_feature(1)..(19)RNA 1566gcaggacuac cugucucugt t 21156721DNAHomo sapiensmisc_feature(1)..(19)RNA 1567gggcagagac agguagucct t 21156821DNAHomo sapiensmisc_feature(1)..(19)RNA 1568ggacuaccug ucucugccct t 21156921DNAHomo sapiensmisc_feature(1)..(19)RNA 1569agggggcaga gacagguagt t 21157021DNAHomo sapiensmisc_feature(1)..(19)RNA 1570cuaccugucu cugcccccut t 21157121DNAHomo sapiensmisc_feature(1)..(19)RNA 1571ccaagggggc agagacaggt t 21157221DNAHomo sapiensmisc_feature(1)..(19)RNA 1572ccugucucug cccccuuggt t 21157321DNAHomo sapiensmisc_feature(1)..(19)RNA 1573uagauguugg ucauaauucg g 21157421DNAHomo sapiensmisc_feature(1)..(19)RNA 1574gaauuaugac caacaucuat t 21157523DNAHomo sapiensmisc_feature(1)..(21)RNA 1575aaaaaugagc cggauggccu utt 23157623DNAHomo sapiensmisc_feature(1)..(21)RNA 1576aaggccaucc ggcucauuuu utt 23157723DNAHomo sapiensmisc_feature(1)..(21)RNA 1577aaaggcguag aucaccgggu utt 23157823DNAHomo sapiensmisc_feature(1)..(21)RNA 1578aacccgguga ucuacgccuu utt 23157919DNAHomo sapiensmisc_featureNucleotides at positions 1, 2, 16, 17, 18 and 19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1579gaccgagctg gccacctcc 19158019DNAHomo sapiensmisc_featureNucleotides at positions 1-3, 8-10, and 17-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1580gaccgagctg gccacctcc 19158120DNAHomo sapiensmisc_featureNucleotides at positions 1, 2, 3, 4, 5, 6, 15, 16, 17, 18, 19 and 20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1581ctctccactt ccacggcctg 20158220DNAHomo sapiensmisc_featureNucleotides 1, 2, and 17-20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1582ctctccactt ccacggcctg 20158320DNAHomo sapiensmisc_featureNucleotides at positions 17-20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1583ctctccactt ccacggcctg 20158420DNAHomo sapiensmisc_featureNucleotides at positions 1-3 and 18-20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1584ctctccactt ccacggcctg 20158520DNAHomo sapiensmisc_featureNucleotides at positions 1, 2, 8-10, and 17-20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1585ctctccactt ccacggcctg 20158620DNAHomo sapiensmisc_featureNucleotides at positions 1, 3, 5, 16, 18, and 20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1586ctctccactt ccacggcctg 20158720DNAHomo sapiensmisc_featureNucleotides at positions 8-13 are 2'-deoxy-2'-fluoro-arabinonucleotides 1587ctctccactt ccacggcctg 20158820DNAHomo sapiensmisc_featureNucleotides at positions 6-8 and 13-15 are 2'-deoxy-2'-fluoro-arabinonucleotides 1588ctctccactt ccacggcctg 20158920DNAHomo sapiensmisc_featureNucleotides at positions 6-8 and 13-15 are 2'-deoxy-2'fluoro-arabinonucleotides 1589ctctccactt ccacggcctg 20159020DNAHomo sapiensmisc_featureNucleotides at positions 1-3 and 18-20 are 2'-deoxy-2'fluoro-arabinonucleotides 1590ctctccactt ccacggcctg 20159120DNAHomo sapiensmisc_featureNucleotides at positions, 2, 4, 6, 8, 10, 12, 14, 16, 18 ad 20 are 2'-deoxy-2'fluoro-arabinonucleotides 1591ctctccactt ccacggcctg 20159220DNAHomo sapiensmisc_featureNucleotides at positions 1, 2, 5, 6, 9, 10, 13, 14, and 17-20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1592ctctccactt ccacggcctg 20159320DNAHomo sapiensmisc_featureNucleotides at positions 6, 7, 14, and 15 are 2'-deoxy-2'-fluoro-arabinonucleotides 1593ctctccactt ccacggcctg 20159420DNAHomo sapiensmisc_featureNucleotides at positions 6-8 and 13-15 are 2'-deoxy-2'-fluoro-arabinonucleotides 1594ctctccactt ccacggcctg 20159520DNAHomo sapiensmisc_featureNucleotides at positions 6-8 and 13-15 are 2'-deoxy-2'-fluoro-arabinonucleotides 1595ctctccactt ccacggcctg 20159620DNAHomo sapiensmisc_featureNucleotides at positions 8-13 are 2'-deoxy-2'-fluoro-arabinonucleotides 1596ctctccactt ccacggcctg 20159720DNAHomo sapiensmisc_featureNucleotides at positions 8-13 are 2'-deoxy-2'-fluoro-arabinonucleotides 1597ctctccactt ccacggcctg 20159820DNAHomo sapiensmisc_featureNucleotides at positions 8-13 are 2'-deoxy-2'-fluoro-arabinonucleotides 1598ctctccactt ccacggcctg 20159919DNAHomo sapiensmisc_featureNucleotides 1-6 and 14-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1599cacctctgtc accagcatg 19160019DNAHomo sapiensmisc_featureNucleotides 1-8 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1600cacctctgtc accagcatg 19160119DNAHomo sapiensmisc_featureNucleotides 1-5, 7-10, 18 and 19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1601cacctgtgtc accagcatg 19160219DNAHomo sapiensmisc_featureNucleotides 17-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1602cacctctgtc accagcatg 19160319DNAHomo

sapiensmisc_featureNucleotides 1, 2 and 17-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1603cacctctgtc accagcatg 19160419DNAHomo sapiensmisc_featureNucleotides 1-4 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1604cacctctgtc accagcatg 19160519DNAHomo sapiensmisc_featureNucleotides 1-4, 8, 9, and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1605cacctctgtc accagcatg 19160619DNAHomo sapiensmisc_featureNucleotides 1, 3, 5, 7, 9, 1, 13, 15, 17 and 19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1606cacctctgtc accagcatg 19160719DNAHomo sapiensmisc_featureNucleotides 1, 2, 5, 6, 9, 10, 13, 14, and 17-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1607cacctctgtc accagcatg 19160819DNAHomo sapiensmisc_featureNucleotides 1-8 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1608cacctctgtc accagcatg 19160919DNAHomo sapiensmisc_featureNucleotides 1-8 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1609cacctctgtc accagcatg 19161019DNAHomo sapiensmisc_featureNucleotides 1-8 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1610cacctctgtc accagcatg 19161119DNAHomo sapiensmisc_featureNucleotides 1-8 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1611cacctctgtc accagcatg 19161219DNAHomo sapiensmisc_featureNucleotides 1-6 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1612cacctctgtc accagcatg 19161319DNAHomo sapiensmisc_featureNucleotides 1-8 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1613cacctctgtc accagcatg 19161419DNAHomo sapiensmisc_featureNucleotides 1-8 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1614cacctctgtc accagcatg 19161519DNAHomo sapiensmisc_featureNucleotides 1-8 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1615cacctctgtc nccngcatg 19161619DNAHomo sapiensmisc_featureNucleotides 1-6 and 16-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1616cacctctgtc accagcatg 19161720DNAHomo sapiensmisc_featureNucleotides 1, 2 and 16-20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1617gaatgggatg tatctgccca 20161820DNAHomo sapiensmisc_featureNucleotides 1, 2, 11, 12, and 18-20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1618gaatgggatg tatctgccca 20161920DNAHomo sapiensmisc_featureNucleotides 1, 2, and 16-20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1619accaggtcca gatgcttgct 20162020DNAHomo sapiensmisc_featureNucleotides 1, 2, 9, 10, and 18-20 are 2'-deoxy-2'-fluoro-arabinonucleotides 1620accaggtcca gatgcttgct 20162120DNAHomo sapiensmisc_featureAll nucleotides are linked by phosphorothioate linkages 1621ctctccnctt ccncggcctg 20162219DNAHomo sapiensmisc_featureAll nucleotides are linked by phosphorothioate linkages 1622gnccgngctg gccncctcc 19162320DNAHomo sapiensmisc_featureAll nucleotides are linked by phosphorothioate linkages 1623tccnctggcc ngcccnggnc 20162421DNAHomo sapiensmisc_featureAll nucleotides are linked by phosphorothioate linkages 1624nngngtcctg nngccgcttg t 21162520DNAHomo sapiensmisc_featureAll nucleotides are linked by phosphorothioate linkages 1625ntngccncng ggctgtcctt 20162618DNARattus norvegicusmisc_featureAll nucleotides are linked by phosphorothioate linkages 1626tggcacttta ggtggctg 18162718DNARattus norvegicusmisc_featureNucleotides 1, 2 and 14-18 are 2'-deoxy-2'-fluoro-arabinonucleotides 1627tggcacttta ggtggctg 18162818DNARattus norvegicusmisc_featureAll nucleotides are linked by phosphorothioate linkages 1628actcatattc atagggtg 18162918DNARattus norvegicusmisc_featureNucleotides 1, 2, and 15-18 are 2'-deoxy-2'-fluoro-arabinonucleotides 1629actcatattc atagggtg 18163019DNAHomo sapiensmisc_featureAll nucleotides are linked by phosphorothioate linkages 1630gggtctgcng cgggntggt 19163121DNAHomo sapiensmisc_featureAll nucleotides are linked by phosphorothioate linkages 1631gttnctnctt ccncctgcct g 21163219DNAHomo sapiensmisc_featureNucleotides 1, 2 and 15-19 are 2'-deoxy-2'-fluoro-arabinonucleotides 1632ggttgctcag ntctgcaca 19163321DNAHomo sapiensmisc_featureNucleotides 1, 2 and 18-21 are 2'-deoxy-2'-fluoro-arabinonucleotides 1633tcatgagtgg cagctgcaat t 21163422RNAHomo sapiens 1634uuguacaugg uaggcuuuca uu 22163522RNAHomo sapiens 1635ugaaggucua cugugugcca gg 22163621RNAHomo sapiens 1636auccuugcua ucugggugcu a 21163722RNAHomo sapiens 1637aaugcaccug ggcaaggauu ca 22163822RNAHomo sapiens 1638auucuaauuu cuccacgucu uu 22163922RNAHomo sapiens 1639aagaugugga aaaauuggaa uc 22164022RNAHomo sapiens 1640aaaaguaauu gugguuuugg cc 22164122RNAHomo sapiens 1641caagaaccuc aguugcuuuu gu 22164223RNAHomo sapiens 1642acuccauuug uuuugaugau gga 23164322RNAHomo sapiens 1643caucaucguc ucaaaugagu cu 22164421RNAHomo sapiens 1644cuuuuugcgg ucugggcuug c 21164522RNAHomo sapiens 1645aagcccuuac cccaaaaagc au 22164622RNAHomo sapiens 1646uggagagaaa ggcaguuccu ga 22164722RNAHomo sapiens 1647aggggcuggc uuuccucugg uc 22164824RNAHomo sapiens 1648agcagaagca gggagguucu ccca 24164923RNAHomo sapiens 1649cgcauccccu agggcauugg ugu 23165020RNAHomo sapiens 1650acugccccag gugcugcugg 20165123RNAHomo sapiens 1651ucccuguccu ccaggagcuc acg 23165223RNAHomo sapiens 1652ugagcgccuc gacgacagag ccg 23165322RNAHomo sapiens 1653agaggcuggc cgugaugaau uc 22165422RNAHomo sapiens 1654gucauacacg gcucuccucu cu 22165520RNAHomo sapiens 1655ccauggaucu ccaggugggu 20165622RNAHomo sapiens 1656caaccuggag gacuccaugc ug 22165722RNAHomo sapiens 1657augcugacau auuuacuaga gg 22165821RNAHomo sapiens 1658ucuaguaaga guggcagucg a 21165924RNAHomo sapiens 1659acugggggcu uucgggcucu gcgu 24166019RNAHomo sapiens 1660ucuaggcugg uacugcuga 19166122RNAHomo sapiens 1661aaaccugugu uguucaagag uc 22166224RNAHomo sapiens 1662ugccuggguc ucuggccugc gcgu 24166321RNAHomo sapiens 1663cccggagcca ggaugcagcu c 21166421RNAHomo sapiens 1664acucuagcug ccaaaggcgc u 21166522RNAHomo sapiens 1665ucuacaaagg aaagcgcuuu cu 22166622RNAHomo sapiens 1666aguuuugcau aguugcacua ca 22166723RNAHomo sapiens 1667ugugcaaauc uaugcaaaac uga 23166823RNAHomo sapiens 1668uaaagugcuu auagugcagg uag 23166922RNAHomo sapiens 1669acugcauuau gagcacuuaa ag 22167023RNAHomo sapiens 1670caaagugcuc auagugcagg uag 23167122RNAHomo sapiens 1671acuguaguau gggcacuucc ag 22167222RNAHomo sapiens 1672agagcuuagc ugauugguga ac 22167321RNAHomo sapiens 1673uucacagugg cuaaguucug c 21167421RNAHomo sapiens 1674uaaagugcug acagugcaga u 21167522RNAHomo sapiens 1675ccgcacugug gguacuugcu gc 22167622RNAHomo sapiens 1676cugaagcuca gagggcucug au 22167722RNAHomo sapiens 1677ucggauccgu cugagcuugg cu 22167822RNAHomo sapiens 1678ugugacuggu ugaccagagg gg 22167923RNAHomo sapiens 1679agcugguguu gugaaucagg ccg 23168022RNAHomo sapiens 1680gcuauuucac gacaccaggg uu 22168122RNAHomo sapiens 1681aaaguucuga gacacuccga cu 22168222RNAHomo sapiens 1682ucagugcacu acagaacuuu gu 22168323RNAHomo sapiens 1683ucuggcuccg ugucuucacu ccc 23168421RNAHomo sapiens 1684agggagggac gggggcugug c 21168522RNAHomo sapiens 1685uagguuaucc guguugccuu cg 22168622RNAHomo sapiens 1686aaucauacac gguugaccua uu 22168723RNAHomo sapiens 1687uuaaugcuaa ucgugauagg ggu 23168822RNAHomo sapiens 1688cuccuacaua uuagcauuaa ca 22168924RNAHomo sapiens 1689uuuggcaaug guagaacuca cacu 24169021RNAHomo sapiens 1690ugguucuaga cuugccaacu a 21169121RNAHomo sapiens 1691caucccuugc augguggagg g 21169221RNAHomo sapiens 1692cucccacaug caggguuugc a 21169322RNAHomo sapiens 1693uucccuuugu cauccuaugc cu 22169422RNAHomo sapiens 1694uucccuuugu cauccuucgc cu 22169522RNAHomo sapiens 1695ugccugucua cacuugcugu gc 22169622RNAHomo sapiens 1696acagcaggca cagacaggca gu 22169722RNAHomo sapiens 1697cuggcccucu cugcccuucc gu 22169822RNAHomo sapiens 1698gcugacuccu aguccagggc uc 22169922RNAHomo sapiens 1699agagguugcc cuuggugaau uc 22170022RNAHomo sapiens 1700aucacacaaa ggcaacuuuu gu 22170123RNAHomo sapiens 1701agguuguccg uggugaguuc gca 23170222RNAHomo sapiens 1702aagacgggag gaaagaaggg ag 22170321RNAHomo sapiens 1703ucacuccucu ccucccgucu u 21170424RNAHomo sapiens 1704cugaagugau guguaacuga ucag 24170523RNAHomo sapiens 1705acuuacagac aagagccuug cuc 23170622RNAHomo sapiens 1706uggucuagga uuguuggagg ag 22170723RNAHomo sapiens 1707cuaauaguau cuaccacaau aaa 23170821RNAHomo sapiens 1708aggaggcagc gcucucagga c 21170923RNAHomo sapiens 1709ggcagguucu cacccucucu agg 23171025RNAHomo sapiens 1710ggcggaggga aguagguccg uuggu 25171122RNAHomo sapiens 1711aggcggggcg ccgcgggacc gc 22171220RNAHomo sapiens 1712guagaggaga uggcgcaggg 20171321RNAHomo sapiens 1713uccucuucuc ccuccuccca g 21171423RNAHomo sapiens 1714cgggucggag uuagcucaag cgg 23171521RNAHomo sapiens 1715cgcgggugcu uacugacccu u 21171621RNAHomo sapiens 1716aaggcagggc ccccgcuccc c 21171722RNAHomo sapiens 1717uauugcacau uacuaaguug ca 22171822RNAHomo sapiens 1718caauuuagug ugugugauau uu 22171923RNAHomo sapiens 1719uuauugcuua agaauacgcg uag 23172021RNAHomo sapiens 1720cauaaaguag aaagcacuac u 21172123RNAHomo sapiens 1721uguaguguuu ccuacuuuau gga 23172223RNAHomo sapiens 1722aacauucaac gcugucggug agu 23172322RNAHomo sapiens 1723accaucgacc guugauugua cc 22172423RNAHomo sapiens 1724aacauucauu gcugucggug ggu 23172522RNAHomo sapiens 1725aacauucaac cugucgguga gu 22172622RNAHomo sapiens 1726aaccaucgac cguugagugg ac 22172723RNAHomo sapiens 1727aacauucauu guugucggug ggu 23172822RNAHomo sapiens 1728uauacaaggg cagacucucu cu 22172923RNAHomo sapiens 1729ucaagagcaa uaacgaaaaa ugu 23173022RNAHomo sapiens 1730uuuuucauua uugcuccuga cc 22173121RNAHomo sapiens 1731gaacggcuuc auacaggagu u 21173222RNAHomo sapiens 1732cuccuauaug augccuuucu uc 22173322RNAHomo sapiens 1733guagauucuc cuucuaugag ua 22173421RNAHomo sapiens 1734aucauagagg aaaauccacg u 21173522RNAHomo sapiens 1735aucauagagg aaaauccaug uu 22173622RNAHomo sapiens 1736uauacaaggg caagcucucu gu 22173722RNAHomo sapiens 1737gaaguuguuc gugguggauu cg 22173823RNAHomo sapiens 1738agguuacccg agcaacuuug cau 23173922RNAHomo sapiens 1739gaauguugcu cggugaaccc cu 22174022RNAHomo sapiens 1740uuuugcaaua uguuccugaa ua 22174122RNAHomo sapiens 1741uugggaucau uuugcaucca ua 22174222RNAHomo sapiens 1742uucacaagga ggugucauuu au 22174322RNAHomo sapiens 1743cucuagaggg aagcgcuuuc ug 22174422RNAHomo sapiens 1744aaaaugguuc ccuuuagagu gu 22174522RNAHomo sapiens 1745aaacauucgc ggugcacuuc uu 22174622RNAHomo sapiens 1746aaaaguaauu gcgaguuuua cc 22174722RNAHomo sapiens 1747caaaacuggc aauuacuuuu gc 22174822RNAHomo sapiens 1748aaaaguaauu gcgguuuuug cc 22174922RNAHomo sapiens 1749caaaaaucuc aauuacuuuu gc 22175022RNAHomo sapiens 1750aaaaguaauu gugguuuuug cc 22175122RNAHomo sapiens 1751caaaaaccac aguuucuuuu gc 22175222RNAHomo sapiens 1752aaaaguaauc gcgguuuuug uc 22175322RNAHomo sapiens 1753aaaaguaauu gcggauuuug cc 22175422RNAHomo sapiens 1754aaaaguaauu gcggucuuug gu 22175522RNAHomo sapiens 1755aaaaguauuu gcggguuuug uc 22175622RNAHomo sapiens 1756caaaaguaau uguggauuuu

gu 22175722RNAHomo sapiens 1757uagcaaaaac ugcaguuacu uu 22175822RNAHomo sapiens 1758cgaaaacagc aauuaccuuu gc 22175921RNAHomo sapiens 1759uaaaguaaau augcaccaaa a 21176024RNAHomo sapiens 1760aaagacauag gauagaguca ccuc 24176122RNAHomo sapiens 1761uggugggccg cagaacaugu gc 22176222RNAHomo sapiens 1762uaugucugcu gaccaucacc uu 22176322RNAHomo sapiens 1763cuugguucag ggaggguccc ca 22176423RNAHomo sapiens 1764aggaagcccu ggaggggcug gag 23176521RNAHomo sapiens 1765uccgguucuc agggcuccac c 21176623RNAHomo sapiens 1766caguaacaaa gauucauccu ugu 23176722RNAHomo sapiens 1767uggauuucuu ugugaaucac ca 22176822RNAHomo sapiens 1768uggugguuua caaaguaauu ca 22176921RNAHomo sapiens 1769uuaauaucgg acaaccauug u 21177020RNAHomo sapiens 1770gugucugggc ggacagcugc 20177120RNAHomo sapiens 1771ugagcccugu ccucccgcag 20177227RNAHomo sapiens 1772auugaucauc gacacuucga acgcaau 27177322RNAHomo sapiens 1773agaucagaag gugauugugg cu 22177423RNAHomo sapiens 1774uaauccuugc uaccugggug aga 23177522RNAHomo sapiens 1775augcaccugg gcaaggauuc ug 22177621RNAHomo sapiens 1776aagccugccc ggcuccucgg g 21177721RNAHomo sapiens 1777acagucugcu gagguuggag c 21177820RNAHomo sapiens 1778guguguggaa augcuucugc 20177919DNAHomo sapiens 1779ctggctcgac cggtggagg 19178020DNAHomo sapiens 1780gagaggtgaa ggtgccggac 20178122DNAHomo sapiens 1781gtctccggtg aggtcccagg ag 22178219DNAHomo sapiens 1782gtggagacag tggtcgtac 19178319DNAHomo sapiens 1783gtggagacag tggtcgtac 19178421DNAHomo sapiens 1784catgaaggcc ttggagagag g 21178518DNAHomo sapiens 1785atatccttgt cgtatccc 18

Claims

1. An oligonucleotide directed against a nucleic acid sequence coding for a protein selected from the group consisting of a CCR3 chemokine receptor and a common beta sub-unit of IL-3, IL-5 and GM-CSF receptors, wherein the oligonucleotide is one of (i) having a base sequence corresponding to any one of SEQ ID NOs. 1-698 and (ii) a modified oligonucleotide of any one of SEQ ID NOs. 1-698.

2. The oligonucleotide of claim 1, wherein the oligonucleotide has the base sequence corresponding to any one of SEQ ID NOs. 1-698.

3. The oligonucleotide of claim 1, wherein at least one adenosine nucleotide of the oligonucleotide is substituted with 2-amino-2'-deoxyadenosine (DAP) or an analog thereof.

4. The oligonucleotide of claim 1, wherein at least one adenosine nucleotide of the oligonucleotide is substituted with 2-amino-2' deoxyadenosine (DAP) or an analog thereof.

5. The oligonucleotide of claim 4, wherein the arabinose modified nucleotide has a 2' substituent selected from the group consisting of fluorine, hydroxyl, amino, azido, alkyl, alkoxy, and alkoxyalkyl groups.

6.-7. (canceled)

8. The oligonucleotide of claim 4, wherein the at least one arabinose modified nucleotide is 2'-deoxy-2'-fluoroarabinonucleotide (FANA).

9. The oligonucleotide of claim 8, wherein the at least one arabinose modified nucleotide is at the 5' end of the oligonucleotide.

10. The oligonucleotide of claim 8, wherein the at least one arabinose modified nucleotide is at the 3' end of the oligonucleotide.

11. The oligonucleotide of claim 8, having at least two arabinose modified nucleotides at both the 5' end and 3' end of the oligonucleotide.

12. The oligonucleotide of claim 11, having between 1-7 arabinose modified nucleotides independently at the 5' end and 3' end of the oligonucleotide.

13. The oligonucleotide of claim 11, having between 1-6 arabinose modified nucleotides independently at the 5' end and 3' end of the oligonucleotide.

14. The oligonucleotide of claim 11, having between 1-5 arabinose modified nucleotides independently at the 5' end and 3' end of the oligonucleotide.

15. The oligonucleotide of claim 11, having between 1-4 arabinose modified nucleotides independently at the 5' end and 3' end of the oligonucleotide.

16. The oligonucleotide of claim 11, having between 1-3 arabinose modified nucleotides independently at the 5' end and 3' end of the oligonucleotide.

17. The oligonucleotide of claim 1, containing at least one internucleotide linkage selected from the group consisting of phosphodiester, phosphotriester, phosphorothioate, methylphosphonate, boranophosphate and any combination thereof.

18. The oligonucleotide of claim 1, wherein the oligonucleotide is one of SEQ ID NOs. 1-698.

19. The oligonucleotide of claim 18, wherein the oligonucleotide is one of SEQ ID NOs. 13 and 683.

20. A pharmaceutical composition comprising at least one of the oligonucleotide of claim 1 and pharmaceutically acceptable carrier.

21.-23. (canceled)

24. A method for treating and/or preventing at least one of asthma, COPD, allergy, CF, hypereosinophilia, general inflammation and cancer in a patient comprising administering to said patient the pharmaceutical composition of claim 20.

25.-72. (canceled)

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