Antisense oligonucleotide targeting atn1 mRNA or pre-mRNA

Abstract

To provide an antisense oligonucleotide targeting atrophin-1 mRNA or pre-mRNA, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.SOLUTION: The present invention provides an antisense oligonucleotide that is formed of 15-22 nucleotides and that is complementary to a nucleic acid comprising at least 15 consecutive bases within a region among a group of specific regions selected from a sequence of human atrophin-1 mRNA, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an antisense oligonucleotide targeting ATN1 mRNA or pre-mRNA, or a pharma- ceutical acceptable salt or hydrate thereof, a pharmaceutical composition comprising the antisense oligonucleotide or a pharma- ceutical acceptable salt or hydrate thereof, etc. [Background technology]

[0002] Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive disease that causes ataxia, involuntary movements called myoclonus, epilepsy, and progressive intellectual deterioration in children, and ataxia, choreoathetosis, dementia, and personality changes in adults (Non-Patent Document 1).

[0003] DRPLA is a repeat disease caused by abnormal expansion of repeat sequences in the genome of a specific gene, resulting in abnormal function of RNA and proteins. DRPLA is known as a repeat disease in which proteins are toxic. DRPLA is divided into adult type, which develops after the age of 20, and pediatric type, which develops before the age of 20, depending on the time of onset. However, patients with approximately 65 or more repeats develop early-onset pediatric type, which is more severe.

[0004] Currently, there are drugs to treat the symptoms of DRPLA, such as epilepsy, psychiatric symptoms, and ataxia, but the treatment has low satisfaction rates and does not address the molecular mechanisms underlying DRPLA. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Liana Veneziano et al., GeneReviews [Internet] 1999 Aug 6 [updated 2016 Jun 9], 1993-2021. Summary of the Invention

[0006] Under these circumstances, it is desired to provide a therapeutic agent for DRPLA that has a more excellent therapeutic effect.

[0007] The present invention provides an antisense oligonucleotide targeting the ATN1 mRNA or pre-mRNA described below, or a pharma- ceutical acceptable salt or hydrate thereof, a pharmaceutical composition comprising the antisense oligonucleotide or a pharma- ceutical acceptable salt or hydrate thereof, and the like.

[0008] (1-1) positions 1 to 84, 142 to 168, 197 to 224, 286 to 317, 324 to 370, 391 to 434, 519 to 540, 623 to 643, 690 to 780, 824 to 855, 860 to 897, 948 to 987, 1044 to 1072, 1125 to 1174, 1181 to 1236, 1182 to 1238, 1183 to 1239, 1190 to 1240, 1191 to 1241, 1192 to 1245, 1193 to 1246, 1194 to 1247, 1195 to 1248, 1196 to 1249, 1250 to 1251, 1252 to 1253, 1254 to 1255, 1256 to 1257, 1258 to 1260, 1262 to 1263, 1264 to 1265, 1266 to 1267, 1268 to 1270, 1272 to 1271, 1276 to 1272, 1278 to 1273, 1279 to 1281, 1282 to 1282, 1284 to 1285, 1286 to 1286, 1288 to 1290, 1300 to 1301, 1302 to 1303, 1304 to 1304, 130 13th, 1228th ~ 1255th, 1265th ~ 1327th, 1334th ~ 1356th, 1416th ~ 1440th, 1447th ~ 1631st, 1638th ~ 1667th, 1675th ~ 1 705th, 1748th ~ 1823rd, 1838th ~ 1861st, 1870th ~ 1913th, 1920th ~ 1941st, 2000th ~ 2040th, 2047th ~ 2075th, 2086th ~ 2 120th, 2129th ~ 2187th, 2194th ~ 2415th, 2451st ~ 2497th, 2592nd ~ 2759th, 2766th ~ 2870th, 2928th ~ 2948th, 2955th ~ 2989th, 3021st ~ 3086th, 3133rd ~ 3209th, 3217th ~ 3284th, 3295th ~ 3350th, 3384th ~ 3436th, 3562nd ~ 3771st, 3858th ~ An antisense oligonucleotide consisting of 15 to 22 nucleotides, which is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 3905, 3931 to 4039, 4067 to 4134, 4170 to 4232, 4241 to 4283, and 4286 to 4355, or a pharma- ceutically acceptable salt or hydrate thereof. (1-2) positions 1 to 84, 142 to 168, 391 to 434, 697 to 780, 962 to 980, 1125 to 1174, 1181 to 1213, 1228 to 1255, 1265 to 1320, 1454 to 1631, 1682 to 1705, 1748 to 1816, 1870 to 1913, 2015 to 2040, 2086 to 2120, 2129 to 2187, 2201 to 2408, 2592 to 2759, 2773 to 287 in the base sequence of SEQ ID NO: 471 The antisense oligonucleotide according to (1-1), which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 0, 2955 to 2982, 3028 to 3079, 3133 to 3209, 3224 to 3277, 3295 to 3350, 3391 to 3429, 3562 to 3771, 3865 to 3898, 3938 to 4032, 4074 to 4127, and 4170 to 4225, or a pharma- ceutically acceptable salt thereof or a hydrate thereof. (2-1) positions 1 to 69, 331 to 363, 398 to 427, 697 to 773, 867 to 890, 955 to 980, 1132 to 1167, 1272 to 1320, 1454 to 1624, 1682 to 1705, 1748 to 1816, 1877 to 1906, 2007 to 2033, 2093 to 2113, 2136 to 2180, 2201 to 2408, 2458 to 2490, 2599 to 2752, 2773 to 2863, 2962 to 2982, 2973 to 2983, 2974 to 2976, 2977 to 2984, 2979 to 2986, 3000 to 3000, 3001 to 3000, 3002 to 3000, 3003 to 3000, 3004 to 3000, 3005 to 3000, 3006 to 3000, 3007 to 3000, 3008 to 3000, 3009 to 3000, 3001 to 3000, 3002 to 3000, 3003 to 3000, 3004 to 3000, 3005 to 3000, 3006 to 3000, 3007 to 3000, 3009 to 3000, 3009 to 3000, 300 The antisense oligonucleotide according to (1-1), or a pharma- ceutically acceptable salt or hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 3028 to 3079, 3140 to 3202, 3224 to 3277, 3302 to 3343, 3391 to 3429, 3569 to 3764, 3865 to 3898, 3938 to 4032, 4074 to 4127, 4177 to 4225, 4248 to 4276, and 4293 to 4355. (2-2) positions 1 to 69, 398 to 427, 697 to 773, 1132 to 1167, 1272 to 1320, 1454 to 1624, 1682 to 1705, 1748 to 1816, 1877 to 1906, 2093 to 2113, 2136 to 2180, 2201 to 2408, 2599 to 2752, 2773 to 2863, 2962 to 2982, 3028 to 3032, 3036 to 3036, 3036 to 3038, 3036 to 3036 ... The antisense oligonucleotide according to (1-1), or a pharma- ceutically acceptable salt or hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 079, 3140 to 3202, 3224 to 3277, 3302 to 3343, 3391 to 3429, 3569 to 3764, 3865 to 3898, 3938 to 4032, and 4177 to 4225. (3) positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 432, 723 to 742, 747 to 778, 965 to 984, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1228 to 1254, 1270 to 1308, 1484 to 1564, 1570 to 1608, 1615 to 1620, 1621 to 1625, 1630 to 1640, 1641 to 1642, 1643 to 1646, 1648 to 1648, 1656 to 1656, 1657 to 1659, 1666 to 1670, 1675 to 1681, 1676 to 1682, 1677 to 1684, 1685 to 1691, 1692 to 1706, 1706 to 1708, 1709 to 1719, 1720 to 1730, 1731 to 1731, 1732 to 1733, 1734 to 1736, 1740 to 1746, 1750 to 1750, 1751 to 1752, 1753 to 1756, 1754 to 1760, 1770 to 1772, 1771 to 1774, 1775 to 1782, 1776 to 1784, 578th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1913th, 2015th to 2034th , 2086th to 2118th, 2129th to 2148th, 2151st to 2184th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 237th 3rd place, 2387th ~ 2406th, 2598th ~ 2757th, 2775th ~ 2809th, 2826th ~ 2866th, 2959th ~ 2982nd, 3032nd ~ 3051st, 3052nd ~ 3071st, 3136th to 3155th, 3168th to 3187th, 3188th to 3207th, 3232nd to 3270th, 3298th to 3344th, 3408th to 3427th, 3563 The antisense oligonucleotide according to (1-1), or a pharma- ceutically acceptable salt or hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 3582 to 3582, 3590 to 3728, 3739 to 3769, 3877 to 3896, 3949 to 4030, and 4170 to 4225. (4) positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 416, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 422, 404 to 423, 405 to 424, 406 to 425, 407 to 426, 408 to 427, 413 to 432, 723 to 742, 747 to 766, 756 to 775, 759 to 778, 965 to 984, 1127 to 1146, 1148 to 1150, 1151 to 1152, 1153 to 1154, 1155 to 1156, 1157 to 1158, 1159 to 1260, 1161 to 1262, 1163 to 1264, 1165 to 1270, 1166 to 1272, 1167 to 1274, 1168 to 1276, 1169 to 1300, 1301 to 1302, 1303 to 1304, 1305 to 1306, 1307 to 1308, 1309 to 1310, 1311 to 1312, 1313 to 1314, 1315 to 1316, 1317 to 1318, 1319 to 1320, 1321 167th, 1151st to 1170th, 1154th to 1173rd, 1182nd to 1201st, 1185th to 1204th, 1188th to 120th 7th place, 1191st to 1210th, 1194th to 1213th, 1228th to 1247th, 1231st to 1250th, 1235th to 1254th, 1270th to 1289th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 1510th, 14 93rd to 1512th, 1506th to 1525th, 1517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1578th ~1597th place, 1579th place~1598th place, 1580th place~1599th place, 1581st~1600th place, 1582nd~1601st, 1583rd~1 602nd, 1584th to 1603rd, 1585th to 1604th, 1586th to 1605th, 1587th to 1606th, 1588th to 160th 7th place, 1589th to 1608th, 1590th to 1609th, 1591st to 1610th, 1592nd to 1611th, 1593rd to 1612th , 1594th to 1613th, 1595th to 1614th, 1596th to 1615th, 1597th to 1616th, 1598th to 1617th, 15 99th to 1618th, 1600th to 1619th, 1601st to 1620th, 1602nd to 1621st, 1603rd to 1622nd, 1604 1623rd ~ 1623rd, 1605th ~ 1624th, 1607th ~ 1626th, 1610th ~ 1629th, 1686th ~ 1705th, 1748th ~ 1 767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1889th, 1871st to 1890th, 1874th to 189th 3rd place, 1877th to 1896th, 1878th to 1897th, 1879th to 1898th, 1880th to 1899th, 1881st to 1900th,1882~1901, 1883~1902, 1884~1903, 1885~1904, 1886~1905, 1887~1906, 1889~1908, 1894~1913, 2015~2034, 2086~2105, 2093 2094~2113, 2097~2116, 2099~2118, 2129~2148, 2151~2170, 2165~2184, 2206~2225, 2239~2258, 2253~2272, 2287~230 6, 2301~2320, 2317~2336, 2337~2356, 2354~2373, 2387~2406, 2598~2617, 2613~2632, 2614~2633, 2615~2634, 2616~2635, 2 617~2636, 2618~2637, 2619~2638, 2620~2639, 2621~2640, 2622~2641, 2623~2642, 2624~2643, 2625~2644, 2626~2645, 2627~ 2646, 2628~2647, 2629~2648, 2630~2649, 2631~2650, 2632~2651, 2633~2652, 2634~2653, 2635~2654, 2636~2655, 2637~2656 2638~2657, 2639~2658, 2640~2659, 2641~2660, 2642~2661, 2643~2662, 2644~2663, 2645~2664, 2646~2665, 2647~2666, 264 8~2667, 2649~2668, 2663~2682, 2672~2691, 2673~2692, 2674~2693, 2675~2694, 2676~2695, 2677~2696, 2678~2697, 2679~2 698, 2680~2699, 2681~2700, 2682~2701, 2683~2702, 2684~2703, 2685~2704, 2686~2705, 2687~2706, 2688~2707, 2689~2708,2690~2709, 2691~2710, 2692~2711, 2693~2712, 2694~2713, 2695~2714, 2696~2715, 2697~2716, 2698~2717, 2699~2718, 2700 2701~2720, 2702~2721, 2703~2722, 2704~2723, 2705~2724, 2706~2725, 2707~2726, 2708~2727, 2709~2728, 2710~272 9, 2711~2730, 2712~2731, 2713~2732, 2714~2733, 2715~2734, 2716~2735, 2717~2736, 2718~2737, 2719~2738, 2720~2739, 2 721~2740, 2722~2741, 2723~2742, 2724~2743, 2725~2744, 2726~2745, 2727~2746, 2728~2747, 2729~2748, 2730~2749, 2731~ 2750, 2732~2751, 2733~2752, 2738~2757, 2775~2794, 2790~2809, 2826~2845, 2827~2846, 2828~2847, 2829~2848, 2830~2849 2831~2850, 2832~2851, 2833~2852, 2834~2853, 2835~2854, 2836~2855, 2837~2856, 2838~2857, 2839~2858, 2840~2859, 2841~2843 1~2860, 2842~2861, 2843~2862, 2844~2863, 2847~2866, 2959~2978, 2962~2981, 2963~2982, 3032~3051, 3052~3071, 3136~3 155, 3168~3187, 3188~3207, 3232~3251, 3251~3270, 3298~3317, 3302~3321, 3303~3322, 3304~3323, 3305~3324, 3306~3325,3307~3326, 3308~3327, 3309~3328, 3310~3329, 3311~3330, 3312~3331, 3313~3332, 3314~3333, 3315~3334, 3316~3335, 3317 3324~3325, 3326~3328, 3329~3339, 3330~3331, 3331~3332, 3332~3333, 3333~3334, 3334~3335, 3336~3337, 3338~3339, 3340~3341, 3342~3343, 3344~3345, 3408~3427, 3563~358 2, 3590~3609, 3608~3627, 3617~3636, 3618~3637, 3619~3638, 3620~3639, 3621~3640, 3622~3641, 3623~3642, 3624~3643, 3 625~3644, 3626~3645, 3627~3646, 3628~3647, 3629~3648, 3630~3649, 3631~3650, 3632~3651, 3633~3652, 3634~3653, 3635~ 3654, 3636~3655, 3637~3656, 3638~3657, 3639~3658, 3640~3659, 3641~3660, 3642~3661, 3643~3662, 3644~3663, 3645~3664 , 3646~3665, 3647~3666, 3648~3667, 3649~3668, 3650~3669, 3651~3670, 3652~3671, 3653~3672, 3654~3673, 3671~3690, 367 2nd to 3691st, 3673rd to 3692nd, 3674th to 3693rd, 3675th to 3694th, 3676th to 3695th, 3677th to 3696th, 3678th to 3697th, 3679th to 3698th, 3680th to 3699th, 3681st to 3700th, 3682nd to 3 701, 3683~3702, 3684~3703, 3685~3704, 3686~3705, 3687~3706, 3688~3707, 3689~3708, 3690~3709, 3691~3710, 3692~3711,3693~3712, 3694~3713, 3695~3714, 3696~3715, 3697~3716, 3698~3717, 3699~3718, 3700~3719, 3701~3720, 3702~3721, 3703 3704~3723, 3705~3724, 3706~3725, 3707~3726, 3708~3727, 3709~3728, 3739~3758, 3740~3759, 3741~3760, 3742~376 1, 3743rd to 3762nd, 3744th to 3763rd, 3745th to 3764th, 3750th to 3769th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3965th to 3984th, 3966th to 3985th, 3967th to 3986th, 3 968~3987, 3969~3988, 3970~3989, 3971~3990, 3972~3991, 3973~3992, 3974~3993, 3975~3994, 3976~3995, 3977~3996, 3978~ 3997, 3979~3998, 3980~3999, 3981~4000, 3982~4001, 3983~4002, 3984~4003, 3985~4004, 3986~4005, 3987~4006, 3988~4007 3989~4008, 3990~4009, 3991~4010, 3992~4011, 3993~4012, 3994~4013, 3995~4014, 3996~4015, 3997~4016, 3998~4017, 399 9th to 4018th, 4011th to 4030th, 4170th to 4189th, 4173rd to 4192nd, 4176th to 4195th, 4177th to 4196th, 4178th to 4197th, 4179th to 4198th, 4180th to 4199th, 4181st to 4200th, 4182nd to 4 201, 4183~4202, 4184~4203, 4185~4204, 4186~4205, 4187~4206, 4188~4207, 4189~4208, 4190~4209, 4191~4210, 4192~4211,The antisense oligonucleotide according to (3), or a pharma- ceutically acceptable salt or hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 4193 to 4212, 4194 to 4213, 4195 to 4214, 4196 to 4215, 4197 to 4216, 4198 to 4217, 4199 to 4218, 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224, and 4206 to 4225. (5) positions 14 to 33, 34 to 53, 398 to 427, 723 to 742, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1564, 1578 to 1624, 1686 to 1705, and 1748 to 1767 of the base sequence of SEQ ID NO: 471 , 1768th ~ 1787th, 1794th ~ 1813th, 1877th ~ 1906th, 2093rd ~ 2113th, 2151st ~ 2170th, 2206th ~ 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2613th to 2752nd, 2 The antisense oligonucleotide according to (2-1) or (3), which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 775 to 2809, positions 2826 to 2863, positions 2962 to 2982, positions 3032 to 3051, positions 3052 to 3071, positions 3168 to 3187, positions 3232 to 3270, positions 3302 to 3343, positions 3408 to 3427, positions 3590 to 3728, positions 3739 to 3764, positions 3877 to 3896, positions 3949 to 4030, and positions 4177 to 4225, or a pharma- ceutically acceptable salt or hydrate thereof. (6) positions 14 to 33, 34 to 53, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 422, 404 to 423, 405 to 424, 406 to 425, 407 to 426, 408 to 427, 723 to 742, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1506 to 1525, 1 517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1579th to 1598th, 158 0th to 1599th, 1581st to 1600th, 1582nd to 1601st, 1583rd to 1602nd, 1584th to 1603rd, 1585th ~1604th place, 1586th place~1605th place, 1587th place~1606th place, 1588th place~1607th place, 1589th place~1608th place, 1590th place~1 609th, 1591st to 1610th, 1592nd to 1611th, 1593rd to 1612th, 1594th to 1613th, 1595th to 161th 4th place, 1596th to 1615th, 1597th to 1616th, 1598th to 1617th, 1599th to 1618th, 1600th to 1619th 1601st to 1620th, 1602nd to 1621st, 1603rd to 1622nd, 1604th to 1623rd, 1605th to 1624th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1896th, 18 78th to 1897th, 1879th to 1898th, 1880th to 1899th, 1881st to 1900th, 1882nd to 1901st, 1883 ~1902nd, 1884~1903, 1885~1904, 1886~1905, 1887~1906, 2093~ 2112nd, 2094th to 2113th, 2151st to 2170th, 2206th to 2225th, 2239th to 2258th, 2253rd to 22nd 72nd, 2287th to 2306th, 2301st to 2320th, 2317th to 2336th, 2337th to 2356th, 2354th to 2373th 2387th to 2406th, 2613th to 2632nd, 2614th to 2633rd, 2615th to 2634th, 2616th to 2635th,2617~2636, 2618~2637, 2619~2638, 2620~2639, 2621~2640, 2622~2641, 2623~2642, 2624~2643, 2625~2644, 2626~2645, 2627 2646, 2648-2647, 2649-2648, 2630-2649, 2631-2650, 2632-2651, 2633-2652, 2634-2653, 2635-2654, 2636-2655, 2637-265 6, 2638~2657, 2639~2658, 2640~2659, 2641~2660, 2642~2661, 2643~2662, 2644~2663, 2645~2664, 2646~2665, 2647~2666, 2 648~2667, 2649~2668, 2663~2682, 2672~2691, 2673~2692, 2674~2693, 2675~2694, 2676~2695, 2677~2696, 2678~2697, 2679~ 2698, 2680~2699, 2681~2700, 2682~2701, 2683~2702, 2684~2703, 2685~2704, 2686~2705, 2687~2706, 2688~2707, 2689~2708 2690~2709, 2691~2710, 2692~2711, 2693~2712, 2694~2713, 2695~2714, 2696~2715, 2697~2716, 2698~2717, 2699~2718, 270 0~2719, 2701~2720, 2702~2721, 2703~2722, 2704~2723, 2705~2724, 2706~2725, 2707~2726, 2708~2727, 2709~2728, 2710~2 729, 2711~2730, 2712~2731, 2713~2732, 2714~2733, 2715~2734, 2716~2735, 2717~2736, 2718~2737, 2719~2738, 2720~2739,2721~2740, 2722~2741, 2723~2742, 2724~2743, 2725~2744, 2726~2745, 2727~2746, 2728~2747, 2729~2748, 2730~2749, 2731 2750, 2732-2751, 2733-2752, 2775-2794, 2790-2809, 2826-2845, 2827-2846, 2828-2847, 2829-2848, 2830-2849, 2831-285 0, 2832~2851, 2833~2852, 2834~2853, 2835~2854, 2836~2855, 2837~2856, 2838~2857, 2839~2858, 2840~2859, 2841~2860, 2 842~2861, 2843~2862, 2844~2863, 2962~2981, 2963~2982, 3032~3051, 3052~3071, 3168~3187, 3232~3251, 3251~3270, 3302~ 3321, 3303~3322, 3304~3323, 3305~3324, 3306~3325, 3307~3326, 3308~3327, 3309~3328, 3310~3329, 3311~3330, 3312~3331 , 3313~3332, 3314~3333, 3315~3334, 3316~3335, 3317~3336, 3318~3337, 3319~3338, 3320~3339, 3321~3340, 3322~3341, 332 3rd to 3342nd, 3324th to 3343rd, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3618th to 3637th, 3619th to 3638th, 3620th to 3639th, 3621st to 3640th, 3622nd to 3 641, 3623~3642, 3624~3643, 3625~3644, 3626~3645, 3627~3646, 3628~3647, 3629~3648, 3630~3649, 3631~3650, 3632~3651,3633~3652, 3634~3653, 3635~3654, 3636~3655, 3637~3656, 3638~3657, 3639~3658, 3640~3659, 3641~3660, 3642~3661, 3643 3644~3643, 3645~3644, 3646~3665, 3647~3666, 3648~3667, 3649~3668, 3650~3669, 3651~3670, 3652~3671, 3653~367 2, 3654~3673, 3671~3690, 3672~3691, 3673~3692, 3674~3693, 3675~3694, 3676~3695, 3677~3696, 3678~3697, 3679~3698, 3 680~3699, 3681~3700, 3682~3701, 3683~3702, 3684~3703, 3685~3704, 3686~3705, 3687~3706, 3688~3707, 3689~3708, 3690~ 3709, 3691~3710, 3692~3711, 3693~3712, 3694~3713, 3695~3714, 3696~3715, 3697~3716, 3698~3717, 3699~3718, 3700~3719 3701~3720, 3702~3721, 3703~3722, 3704~3723, 3705~3724, 3706~3725, 3707~3726, 3708~3727, 3709~3728, 3739~3758, 374 0~3759, 3741~3760, 3742~3761, 3743~3762, 3744~3763, 3745~3764, 3877~3896, 3949~3968, 3964~3983, 3965~3984, 3966~3 985, 3967~3986, 3968~3987, 3969~3988, 3970~3989, 3971~3990, 3972~3991, 3973~3992, 3974~3993, 3975~3994, 3976~3995,3977th to 3996th, 3978th ​​to 3997th, 3979th to 3998th, 3980th to 3999th, 3981st to 4000th, 3982nd to 4001st, 3983rd to 4002nd, 3984th to 40th 03rd place, 3985th ~ 4004th, 3986th ~ 4005th, 3987th ~ 4006th, 3988th ~ 4007th, 3989th ~ 4008th, 3990th ~ 4009th, 3991st ~ 4010th, 3992nd ~4011st, 3993rd~4012th, 3994th~4013th, 3995th~4014th, 3996th~4015th, 3997th~4016th, 3998th~4017th, 3999th~4018th, 40 11th to 4030th, 4177th to 4196th, 4178th to 4197th, 4179th to 4198th, 4180th to 4199th, 4181st to 4200th, 4182nd to 4201st, 4183rd to 4202nd , 4184th ~ 4203rd, 4185th ~ 4204th, 4186th ~ 4205th, 4187th ~ 4206th, 4188th ~ 4207th, 4189th ~ 4208th, 4190th ~ 4209th, 4191st ~ 4 210th, 4192nd ~ 4211th, 4193rd ~ 4212nd, 4194th ~ 4213th, 4195th ~ 4214th, 4196th ~ 4215th, 4197th ~ 4216th, 4198th ~ 4217th, 4199th The antisense oligonucleotide according to (5), or a pharma- ceutically acceptable salt thereof, or a hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224, and 4206 to 4225. (7) positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 432, 747 to 778, 965 to 984, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1228 to 1254, 1270 to 1308, 1484 to 1564, 1578 to 1629, and 1686 to 1705 of the base sequence of SEQ ID NO: 471 , 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1913th, 2015th to 2034th, 2086th to 2118th, 2129th to 2148th, 215 1st to 2170th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2598th to 2632nd, 2633rd to 2 668th, 2672nd - 2691st, 2699th - 2757th, 2775th - 2809th, 2826th - 2866th, 2959th - 2978th, 3032nd - 3051st, 3052nd - 3071st 3136th to 3155th, 3168th to 3187th, 3188th to 3207th, 3232nd to 3270th, 3298th to 3317th, 3325th to 3344th, 3408th to 3427th, 35th The antisense oligonucleotide according to (3), which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 90 to 3690, 3691 to 3728, 3739 to 3769, 3877 to 3896, 3949 to 3983, 3984 to 4030, and 4170 to 4198, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof. (8) positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 416, 413 to 432, 747 to 766, 756 to 775, 759 to 778, 965 to 984, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1173, 1182 to 1201, 1185 to 1204, 1188 to 1207, 1191 to 1210, 1194 to 1213, 1228 to 1247, 1231 to 1250, 1235 to 1248, 1236 to 1249, 1237 to 1251, 1238 to 1252, 1239 to 1260, 1241 to 1263, 1242 to 1244, 1245 to 1246, 1246 to 1248, 1249 to 1252, 1253 to 1254, 1255 to 1256, 1257 to 1259, 1260 to 1261, 1262 to 1263, 1264 to 1265, 1266 to 1267, 1268 to 1269, 1270 to 1270, 1271 to 1271, 1272 to 1273, 1273 to 1274, 1274 to 1275, 1275 254th, 1270th to 1289th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 151th 0th place, 1493rd to 1512th, 1506th to 1525th, 1517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1586th to 1605th, 1589th to 1608th, 1592nd to 1611th, 1595th to 1614th, 15 98th to 1617th, 1601st to 1620th, 1604th to 1623rd, 1607th to 1626th, 1610th to 1629th, 1686th ~1705th place, 1748th place~1767th place, 1768th place~1787th place, 1794th place~1813th place, 1870th place~1889th place, 1871st~1 890th, 1874th to 1893rd, 1877th to 1896th, 1880th to 1899th, 1883rd to 1902nd, 1886th to 190th 5th place, 1889th to 1908th, 1894th to 1913th, 2015th to 2034th, 2086th to 2105th, 2097th to 2116th , 2099th to 2118th, 2129th to 2148th, 2151st to 2170th, 2206th to 2225th, 2239th to 2258th, 22 53rd to 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th to 2336th, 2337th to 2356th, 2354 ~2373rd, 2387~2406, 2598~2617, 2613~2632, 2633~2652, 2649~2 668th, 2672nd ~ 2691st, 2699th ~ 2718th, 2702nd ~ 2721st, 2705th ~ 2724th, 2708th ~ 272th 7th place, 2711th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2723rd to 2742nd,2726th ~ 2745th, 2729th ~ 2748th, 2738th ~ 2757th, 2775th ~ 2794th, 2790th ~ 2809th, 2826th ~ 2845th, 2829 2848th to 2848th, 2832nd to 2851st, 2835th to 2854th, 2838th to 2857th, 2841st to 2860th, 2847th to 2866th, 2959th to 29th 78th place, 3032nd ~ 3051st, 3052nd ~ 3071st, 3136th ~ 3155th, 3168th ~ 3187th, 3188th ~ 3207th, 3232nd ~ 3251st, 3251st to 3270th, 3298th to 3317th, 3325th to 3344th, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th ~3636th, 3635th ~ 3654th, 3654th ~ 3673rd, 3671st ~ 3690th, 3691st ~ 3710th, 3709th ~ 3728th, 3739th ~ 375th 8th place, 3750th to 3769th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3984th to 4003rd, 3999th to 4018th, 4 The antisense oligonucleotide according to (7), or a pharma- ceutically acceptable salt thereof, or a hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 011 to 4030, positions 4170 to 4189, positions 4173 to 4192, positions 4176 to 4195, and positions 4179 to 4198. (9) positions 14 to 33, 34 to 53, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1564, 1578 to 1623, 1686 to 1705, 1748 to 1767, 1768 to 1787, 1794 to 1805, 1816 to 1820, 1822 to 1830, 1836 to 1840, 1846 to 1850, 1852 to 1856, 1856 to 1860, 1864 to 1870, 1876 to 1874, 1876 to 1876, 1878 to 1880, 1886 to 1890, 1894 to 1900, 1906 to 1912, 1908 to 1916, 1918 to 1920, 1922 to 1930, 1936 to 1940, 1940 to 1950, 1952 to 1960, 1960 to 1970, 1970 to 1980, 1982 to 1990, 1994 to 2000, 1996 to 2002, 1998 to 2004, 1998 to 2006, 1999 to 2010, 1999 to 2011, 1999 to 2012, 1999 to 2013, 1999 to 2014, 1999 to 2015, 13th, 1877th to 1905th, 2151st to 2170th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 233 7th to 2373rd, 2387th to 2406th, 2613th to 2632nd, 2633rd to 2668th, 2672nd to 2691st, 2699th to 2748th The antisense oligonucleotide according to (5) or (7), or a pharma- ceutically acceptable salt or hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 2775 to 2809, 2826 to 2860, 3032 to 3051, 3052 to 3071, 3168 to 3187, 3232 to 3270, 3408 to 3427, 3590 to 3690, 3691 to 3728, 3739 to 3758, 3877 to 3896, 3949 to 3983, 3984 to 4030, and 4179 to 4198. (10-1) positions 14 to 33, 34 to 53, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1506 to 1525, 1517 to 1536, 1531 to 1550, 1545 to 1564, 1578 to 1597, 1586 to 1605, 1589 to 1608, 1592 to 1611, 1595 to 1614, 1598 to 1617, and 1601 to 1620 of the base sequence of SEQ ID NO: 471 , 1604th to 1623rd, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1 877th to 1896th, 1880th to 1899th, 1883rd to 1902nd, 1886th to 1905th, 2151st to 2170th, 220 6th to 2225th, 2239th to 2258th, 2253rd to 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th ~2336th, 2337th ~2356th, 2354th ~2373rd, 2387th ~2406th, 2613th ~2632nd, 2633rd~2 652nd, 2649th to 2668th, 2672nd to 2691st, 2699th to 2718th, 2702nd to 2721st, 2705th to 272th 4th place, 2708th to 2727th, 2711th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th , 2723rd to 2742nd, 2726th to 2745th, 2729th to 2748th, 2775th to 2794th, 2790th to 2809th, 2 826th to 2845th, 2829th to 2848th, 2832nd to 2851st, 2835th to 2854th, 2838th to 2857th, 284 1st to 2860th, 3032nd to 3051st, 3052nd to 3071st, 3168th to 3187th, 3232nd to 3251st, 3251st ~3270th, 3408th ~ 3427th, 3590th ~ 3609th, 3608th ~ 3627th, 3617th ~ 3636th, 3635th ~ 3 654th, 3654th to 3673rd, 3671st to 3690th, 3691st to 3710th, 3709th to 3728th, 3739th to 375th 8th place, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3984th to 4003rd, 3999th to 4018th,The antisense oligonucleotide according to (9), which is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 4011 to 4030 and positions 4179 to 4198, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof. (10-2) positions 397 to 416, 759 to 778, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1488 to 1525, 1586 to 1629, 1686 to 1705, 1768 to 1787, 1870 to 1908, 2097 to 2118, 2151 to 2170, 2239 to 2258, 2287 to 2306, 2317 to 2336, 2633 to 2652, 270 The antisense oligonucleotide according to (7), or a pharma- ceutical acceptable salt or hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 2 to 2745, positions 2832 to 2866, positions 2959 to 2978, positions 3298 to 3317, positions 3635 to 3654, positions 3671 to 3690, positions 3691 to 3710, positions 3750 to 3983, positions 3984 to 4003, and positions 4170 to 4198. (10-3) positions 397 to 416, 759 to 778, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1173, 1182 to 1201, 1185 to 1204, 1194 to 1213, 1488 to 1507, 1491 to 1510, 1506 to 1525, 1586 to 1605, 1589 to 1608, 1595 to 1614, and 1598 to 1617 in the base sequence of SEQ ID NO: 471 1601st to 1620th, 1604th to 1623rd, 1607th to 1626th, 1610th to 1629th, 1686th to 1705th, 1768th to 1787th, 1870th to 1889th, 1871st to 1890th, 1874th ~1893rd, 1877th ~ 1896th, 1886th ~ 1905th, 1889th ~ 1908th, 2097th ~ 2116th, 2099th ~ 2118th, 2151st ~ 2170th, 2239th ~ 2258th, 2287th ~ 2306th, 2317th ~ 2336th, 2633rd ~ 2652nd, 2702nd ~ 2721st, 2705th ~ 2724th, 2708th ~ 2727th, 2711th ~ 2730th, 2714th ~ 2733rd, 2717th ~ 2736th, 2720th ~ 2739th, 2726th ~ 2745th, 2832nd ~ 2851st, 2835th ~ 2854th, 2841st ~ 2860th, 2847th ~ 2866th, 2959th ~ 2978th, 3298th ~ 3317th, 3635th ~ 3654th, 3 The antisense oligonucleotide according to (7) or (8), or a pharma- ceutically acceptable salt thereof, or a hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 671 to 3690, 3691 to 3710, 3750 to 3769, 3964 to 3983, 3984 to 4003, 4170 to 4189, 4173 to 4192, 4176 to 4195, and 4179 to 4198. (10-4) The antisense oligonucleotide according to (7), which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 397 to 416, 1194 to 1213, 1506 to 1525, 1586 to 1626, 1870 to 1896, 2097 to 2116, 2317 to 2336, 2633 to 2652, 2702 to 2739, 2841 to 2978, 3298 to 3317, 3635 to 3654, 3691 to 3710, 3750 to 3769, 3984 to 4003, and 4170 to 4198 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt or hydrate thereof. (10-5) positions 397 to 416, 1194 to 1213, 1506 to 1525, 1586 to 1605, 1595 to 1614, 1598 to 1617, 1604 to 1623, 1607 to 1626, 1870 to 1889, 1871 to 1890, 1874 to 1893, 1877 to 1896, 2097 to 2116, 2317 to 2336, 2633 to 2652, 2702 to 2721, 2708 to 2727, 2711 to 2730, 2714 to 2733, 2717 The antisense oligonucleotide according to (7) or (8), or a pharma- ceutically acceptable salt or hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 2736, 2720, 2739, 2841, 2860, 2959, 2978, 3298, 3317, 3635, 3654, 3691, 3710, 3750, 3769, 3984, 4003, 4170, 4189, 4173, 4174, 4175, 4176, 4195, and 4179, 4198. (11) The antisense oligonucleotide according to (7), which is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1598 to 1626, 1870 to 1890, 2097 to 2116, 2711 to 2736, 2841 to 2860, and 4170 to 4198 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof. (12) The antisense oligonucleotide according to (7) or (8), which is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1598 to 1617, 1604 to 1623, 1607 to 1626, 1870 to 1889, 1871 to 1890, 2097 to 2116, 2711 to 2730, 2714 to 2733, 2717 to 2736, 2841 to 2860, 4170 to 4189, 4173 to 4192, and 4179 to 4198 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt or hydrate thereof. (12'-1) The antisense oligonucleotide according to (5), which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 400 to 425, 1581 to 1624, 1878 to 1898, 2094 to 2113, 2629 to 2656, 2700 to 2741, 2839 to 2863, 2962 to 2981, 3302 to 3325, 3631 to 3658, 3687 to 3714, 3745 to 3764, 3980 to 4007, 4177 to 4199, and 4204 to 4223 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt or hydrate thereof. (12'-2) positions 400 to 419, 403 to 422, 406 to 425, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1590 to 1609, 1591 to 1610, 1592 to 1611, 1593 to 1612, 1594 to 1613, 1596 to 1615, 1597 to 1616, 1599 to 1618, 16 00th to 1619th, 1602nd to 1621st, 1603rd to 1622nd, 1605th to 1624th, 1878th to 1897th, 1879th to 1898th, 2094th to 2113th, 2629th to 2648th, 2637th to 2656th, 2700th to 2719th 2701st ~ 2720th, 2703rd ~ 2722nd, 2704th ~ 2723rd, 2706th ~ 2725th, 2707th ~ 2726th, 2709th ~ 2728th, 2710th ~ 2729th, 2712th ~ 2731st, 2713th ~ 2732nd, 2715th ~ 2734th, 2716th to 2735th, 2718th to 2737th, 2719th to 2738th, 2721st to 2740th, 2722 ~2741st, 2839~2858, 2840~2859, 2842~2861, 2843~2862, 28 44th to 2863rd, 2962nd to 2981st, 3302nd to 3321st, 3306th to 3325th, 3631st to 3650th, 3632nd to 3651st, 3633rd to 3652nd, 3634th to 3653rd, 3636th to 3655th, 3637th to 3656th The antisense oligonucleotide according to (5) or (6), or a pharma- ceutically acceptable salt or hydrate thereof, is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 3638 to 3657, 3639 to 3658, 3687 to 3706, 3695 to 3714, 3745 to 3764, 3980 to 3999, 3988 to 4007, 4177 to 4196, 4178 to 4197, 4180 to 4199, and 4204 to 4223. (12'-3) The antisense oligonucleotide according to (5), which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 400 to 425, 1581 to 1624, 1878 to 1898, 2637 to 2656, 2700 to 2741, 2839 to 2863, 2962 to 2981, 3302 to 3325, 3631 to 3658, 3687 to 3706, 3745 to 3764, 4177 to 4199, and 4204 to 4223 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof. (12'-4) positions 400 to 419, 403 to 422, 406 to 425, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1591 to 1610, 1592 to 1611, 1593 to 1612, 1594 to 1613, 1596 to 1615, 1597 to 1616, and 1600 of the base sequence of SEQ ID NO: 471 ~1619th, 1602nd ~ 1621st, 1603rd ~ 1622nd, 1605th ~ 1624th, 1878th ~ 1897th, 1879th ~ 1898th, 2637th ~ 2656th, 2700th ~ 2719th, 2701st ~ 2720th, 27 03rd ~ 2722nd, 2704th ~ 2723rd, 2706th ~ 2725th, 2707th ~ 2726th, 2709th ~ 2728th, 2710th ~ 2729th, 2712th ~ 2731st, 2713th ~ 2732nd, 2715th ~ 2734th, 2716th to 2735th, 2718th to 2737th, 2719th to 2738th, 2721st to 2740th, 2722nd to 2741st, 2839th to 2858th, 2840th to 2859th, 2842nd to 2861st, 2843rd to 286th 2nd place, 2844th - 2863rd, 2962nd - 2981st, 3302nd - 3321st, 3306th - 3325th, 3631st - 3650th, 3632nd - 3651st, 3633rd - 3652nd, 3634th - 3653rd, 3636th - 3 The antisense oligonucleotide according to (5) or (6), which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 655, 3637 to 3656, 3638 to 3657, 3639 to 3658, 3687 to 3706, 3745 to 3764, 4177 to 4196, 4178 to 4197, 4180 to 4199, and 4204 to 4223, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof. (12'-5) The antisense oligonucleotide according to (5), which is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1581 to 1624, 2703 to 2740, 3633 to 3655, and 4177 to 4199 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof. (12'-6) positions 1581 to 1600, 1582 to 1601, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1594 to 1613, 1596 to 1615, 1597 to 1616, 1602 to 1621, 1603 to 1622, 1605 to 1624, 2703 to 2722, 2707 to 2726, 2709 to 2728, 2710 to 2729, 2712 to 2731, 2713 to 2732, 2714 to 2736, 2715 to 2738, 2716 to 2739, 2729 to 2740, 2729 to 2741, 2729 to 2742, 2730 to 2733, 2734 to 2735, 2736 to 2737, 2738 to 2739, 2741 to 2742, 2743 to 2744, 2745 to 2746, 2747 to 2748, 2749 to 2750, 2751 to 2752, 2753 to 2754, 2755 to 2756, 2757 to 2758, 2759 to 2760, 2761 to 2762, 2763 to 2764, 2765 to 2766, 2767 to 2768 The antisense oligonucleotide according to (5) or (6), which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 2, 2715-2734, 2716-2735, 2718-2737, 2719-2738, 2721-2740, 3633-3652, 3634-3653, 3636-3655, 4177-4196, 4178-4197, and 4180-4199, or a pharma- ceutically acceptable salt or hydrate thereof. (12'-7) The antisense oligonucleotide according to (5), which is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1587 to 1616, 2712 to 2735, and 4180 to 4199 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt thereof, or a hydrate of either. (12'-8) The antisense oligonucleotide according to (5) or (6), which is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1587 to 1606, 1597 to 1616, 2712 to 2731, 2716 to 2735, and 4180 to 4199 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof. (13) The antisense oligonucleotide according to any one of (1) to (12), which is complementary to a nucleic acid containing at least 20 consecutive bases of the target region, or a pharma- ceutical acceptable salt thereof, or a hydrate of either. (14)(i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464. The antisense oligonucleotide according to (3) or (4), or a pharma- ceutical acceptable salt thereof, or a hydrate thereof. (15)(i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163 to 464; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163 to 464, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163 to 464. The antisense oligonucleotide according to (5) or (6), or a pharma- ceutical acceptable salt thereof, or a hydrate of the same or the like, (16) (i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163. The antisense oligonucleotide according to (7) or (8), or a pharma- ceutical acceptable salt thereof, or a hydrate of the same or the like, comprising: (17-1)(i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163. The antisense oligonucleotide according to (9) or (10-1), or a pharma- ceutical acceptable salt thereof, or a hydrate of the same or the like, (17-2)(i) a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157, and 160 to 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157, and 160 to 163, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157, and 160 to 163. The antisense oligonucleotide according to (10-2) or (10-3), or a pharma- ceutical acceptable salt thereof, or a hydrate of these. (17-3)(i) a base sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157, and 160 to 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157, and 160 to 163, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157, and 160 to 163. The antisense oligonucleotide according to (10-4) or (10-5), or a pharma- ceutical acceptable salt thereof, or a hydrate of the same or the like, comprising: (18) (i) a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163 The antisense oligonucleotide according to (11) or (12), or a pharma- ceutical acceptable salt thereof, or a hydrate of the same or the like, comprising: (19-1)(i) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355. The antisense oligonucleotide according to (12'-1) or (12'-2), or a pharma- ceutical acceptable salt thereof, or a hydrate of these, comprising: (19-2)(i) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355. The antisense oligonucleotide according to (12'-3) or (12'-4), or a pharma- ceutical acceptable salt thereof, or a hydrate of these, comprising: (19-3)(i) a base sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353. The antisense oligonucleotide according to (12'-5) or (12'-6), or a pharma- ceutical acceptable salt thereof, or a hydrate thereof. (20) (i) a nucleotide sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199, and 221; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199, and 221, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199, and 221 The antisense oligonucleotide according to (12'-7) or (12'-8), or a pharma- ceutical acceptable salt thereof, or a hydrate thereof. (21) The antisense oligonucleotide according to any one of (14) to (20), which contains the base sequence of (i), or a pharma- ceutically acceptable salt thereof, or a hydrate of the two. (22) positions 468 to 487, 474 to 493, 583 to 602, 586 to 605, 619 to 638, 770 to 789, 774 to 793, 775 to 794, 778 to 797, 804 to 823, 851 to 870, 1160 to 1179, 1162 to 1181, 1170 to 1189, 1173 to 1192, 1205 to 1224, 1210 to 1229, 1216 to 1235, 1217 to 1236, 1219 to 1238, and 1385 of the base sequence of SEQ ID NO: 471 An antisense oligonucleotide consisting of 15 to 22 nucleotides, which is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1404, 1441 to 1460, 1818 to 1837, 1902 to 1921, 1905 to 1924, 1908 to 1927, 1914 to 1933, 1931 to 1950, 2117 to 2136, 2749 to 2768, 3100 to 3119, and 4125 to 4144, or a pharma- ceutically acceptable salt or hydrate thereof. (23) (i) a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146, and 159; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146, and 159, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146, and 159. The antisense oligonucleotide according to (22), or a pharma- ceutical acceptable salt thereof, or a hydrate of the same or the like. (24) The antisense oligonucleotide according to (23), which comprises the base sequence of (i), or a pharma- ceutical acceptable salt thereof, or a hydrate of the two. (25) The antisense oligonucleotide according to any one of (1) to (24), or a pharma- ceutical acceptable salt thereof, or a hydrate of the foregoing, wherein the antisense oligonucleotide consists of 20 nucleotides. (26) The antisense oligonucleotide according to any one of (1) to (25), wherein the sugar moiety and / or the phosphate linkage moiety of at least one nucleotide constituting the oligonucleotide is modified, or a pharma- ceutical acceptable salt thereof, or a hydrate of the two. (27-1) The antisense oligonucleotide according to (26), or a pharma- ceutically acceptable salt thereof, or a hydrate thereof, wherein the antisense oligonucleotide is a gapmer comprising a central gap region and two wing regions (5' wing region and 3' wing region) adjacent to the 5' and 3' ends of the gap region. (27-2) The antisense oligonucleotide according to (27-1), or a pharma- ceutically acceptable salt thereof, or a hydrate of either, wherein the antisense oligonucleotide is composed of, from the 5' side to the 3' side, a 5' wing region having a length of 5 nucleotides, a gap region having a length of 10 nucleotides, and a 3' wing region having a length of 5 nucleotides. (28) The antisense oligonucleotide according to (27-1) or (27-2), or a pharma- ceutically acceptable salt or hydrate thereof, wherein all internucleoside bonds are phosphorothioate bonds. (29) The antisense oligonucleotide according to (27-1) or (27-2), or a pharma- ceutically acceptable salt or hydrate thereof, wherein one or more of the bonds between the second and third nucleosides, the bond between the third and fourth nucleosides, and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or one or more of the bonds between the first and second nucleosides, the bond between the second and third nucleosides, and the bond between the third and fourth nucleosides from the 5' side of the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds. (30) The antisense oligonucleotide according to (29), or a pharma- ceutically acceptable salt or hydrate thereof, wherein the bond between the second and third nucleosides and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or the bond between the first and second nucleosides and the bond between the third and fourth nucleosides from the 5' side of the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds. (31) The antisense oligonucleotide according to (29), or a pharma- ceutically acceptable salt or hydrate thereof, wherein the bonds between the second and third nucleosides, the bond between the third and fourth nucleosides, and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or the bonds between the first and second nucleosides, the bond between the second and third nucleosides, and the bond between the third and fourth nucleosides from the 5' side of the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds. (32) The antisense oligonucleotide according to any one of (27-1) to (31), or a pharma- ceutically acceptable salt thereof, or a hydrate of either, wherein the wing region contains a 2'-OMe (2'-O-CH3) group and / or a 2'-O-MOE (2'-O-CH2CH2OCH3) group. (33) A pharmaceutical composition comprising the antisense oligonucleotide according to any one of (1) to (32) or a pharma- ceutical acceptable salt thereof, or a hydrate of the same or the like. (34) The antisense oligonucleotide according to any one of (1) to (32), or a pharma- ceutical acceptable salt or hydrate thereof, or the pharmaceutical composition according to (33), for treating and / or preventing dentatorubral-pallidoluysian atrophy (DRPLA). (35) A method for treating and / or preventing dentatorubral-pallidoluysian atrophy (DRPLA), comprising the step of administering to a subject the antisense oligonucleotide according to any one of (1) to (32) or a pharma- ceutical acceptable salt thereof or a hydrate thereof, or the pharmaceutical composition according to (33) or (34).

[0009] The present invention provides an antisense oligonucleotide targeting ATN1 mRNA or pre-mRNA, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof, and a composition comprising the antisense oligonucleotide, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

[0010] In the present invention, since the mutant ATN1, which is the causative gene of DRPLA, is directly inhibited, a DRPLA therapeutic agent with high therapeutic satisfaction can be provided. In the present invention, since an antisense oligonucleotide can be designed targeting the mutant ATN1, which is the causative gene of DRPLA, a DRPLA therapeutic agent with fewer side effects can be provided according to a preferred embodiment of the present invention. According to one embodiment of the present invention, it is also possible to provide a tailor-made treatment based on the genetic information of each individual patient. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In one embodiment, the present invention relates to a nucleic acid sequence encoding amino acids 1 to 84, 142 to 168, 197 to 224, 286 to 317, 324 to 370, 391 to 434, 519 to 540, 623 to 643, 690 to 780, 824 to 855, 860 to 897, 948 to 987, 1044 to 1072, 1125 to 1174, 1130 to 1135, 1136 to 1137, 1138 to 1139, 1140 to 1142, 1144 to 1146, 1148 to 1149, 1150 to 1151, 1152 to 1153, 1154 to 1155, 1160 to 1162, 1164 to 1166, 1170 to 1174, 1176 to 1178, 1180 to 1182, 1184 to 1186, 1186 to 1188, 1190 to 1200, 1200 to 1201, 1202 to 1203, 1204 to 1205, 1206 to 1207, 1208 to 1209, 1210 to 1211, 1212 to 1213, 1214 to 1215, 1216 to 1217, 1218 to 1219, 1220 to 1221, 1222 to 1224, 1230 to 181st to 1213th, 1228th to 1255th, 1265th to 1327th, 1334th to 1356th, 1416th to 1440th, 1447th to 1631st, 1638th to 1667th, 16 75th to 1705th, 1748th to 1823rd, 1838th to 1861st, 1870th to 1913th, 1920th to 1941st, 2000th to 2040th, 2047th to 2075th, 2086 2120th to 2120th, 2129th to 2187th, 2194th to 2415th, 2451st to 2497th, 2592nd to 2759th, 2766th to 2870th, 2928th to 2948th, 2955th ~2989th, 3021st ~ 3086th, 3133rd ~ 3209th, 3217th ~ 3284th, 3295th ~ 3350th, 3384th ~ 3436th, 3562nd ~ 3771st, 3858th ~ 3 The present invention relates to an antisense oligonucleotide consisting of 15 to 22 nucleotides, which is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 905, 3931 to 4039, 4067 to 4134, 4170 to 4232, 4241 to 4283, and 4286 to 4355, or a pharma- ceutically acceptable salt or hydrate thereof.

[0012] SEQ ID NO: 471 is the sequence of human atrophin-1 (ATN1) mRNA (Gen Bank: NM_001007026). The sequence of SEQ ID NO: 471 is a nucleotide sequence containing 4355 nucleotides, and the region consisting of positions 1691 to 1747 of SEQ ID NO: 1 is a repeat region containing a CAG / CAA repeat sequence. In one embodiment, the target sequence of the antisense oligonucleotide of the present invention does not contain a repeat region containing a CAG / CAA repeat sequence.

[0013] In one embodiment, the antisense oligonucleotides of the invention are complementary to a nucleic acid comprising or consisting of at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, e.g., 20 consecutive bases in the target region.

[0014] In the present specification, an antisense oligonucleotide that is "complementary" to a certain nucleic acid is not limited to an antisense oligonucleotide that forms a Watson-Crick base pair with the target nucleic acid, but also includes an antisense oligonucleotide that forms a wobble base pair. Here, the Watson-Crick base pair means a base pair in which a hydrogen bond is formed between adenine-thymine, adenine-uracil, and guanine-cytosine, and the wobble base pair means a base pair in which a hydrogen bond is formed between guanine-uracil, inosine-uracil, inosine-adenine, and inosine-cytosine. In addition, a "complementary base sequence" does not have to have 100% complementarity with the target base sequence, and may contain, for example, one, two, three, four, or five non-complementary bases relative to the target base sequence, or may be a base sequence that is one, two, three, four, or five bases shorter than the target base sequence. In one embodiment, an antisense oligonucleotide that is "complementary" to a nucleic acid has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% complementarity to the nucleic acid. Complementarity can be easily determined by one of skill in the art, for example, by aligning two sequences, counting the number of bases that form Watson-Crick base pairs or wobble base pairs between the sequences, dividing the number of bases that form base pairs by the total number of bases in the sequences, and multiplying the result by 100.

[0015] An example of an antisense oligonucleotide that is "complementary" to a certain nucleic acid is an antisense oligonucleotide that can hybridize to the nucleic acid, for example, under stringent conditions. In this specification, "stringent conditions" may be low stringent conditions, medium stringent conditions, or high stringent conditions. "Low stringent conditions" are, for example, 5xSSC, 5xDenhardt's solution, 0.5%SDS, 50% formamide, and 32°C. "Medium stringent conditions" are, for example, 5xSSC, 5xDenhardt's solution, 0.5%SDS, 50% formamide, and 42°C, or 5xSSC, 1%SDS, 50mM Tris-HCl (pH7.5), 50% formamide, and 42°C. "Highly stringent conditions" are, for example, 5xSSC, 5xDenhardt's solution, 0.5% SDS, 50% formamide, 50°C or 0.2xSSC, 0.1% SDS, 65°C. Under these conditions, it is expected that the higher the temperature, the more efficiently a base sequence with high sequence identity can be obtained. However, factors that affect the stringency of hybridization include multiple factors such as temperature, probe concentration, probe length, ionic strength, time, and salt concentration, and a person skilled in the art can achieve similar stringency by appropriately selecting these factors.

[0016] When a commercially available kit is used for hybridization, for example, AlkPhos Direct Labeling and Detection System (GE Healthcare) can be used. In this case, the membrane is incubated with the labeled probe overnight according to the protocol attached to the kit, and then washed with a primary washing buffer containing 0.1% (w / v) SDS under conditions of 55°C, after which hybridization can be detected. Alternatively, when a probe is prepared based on a target sequence, if the probe is labeled with digoxigenin (DIG) using a commercially available reagent (e.g., PCR labeling mix (Roche Diagnostics), etc.), hybridization can be detected using a DIG Nucleic Acid Detection Kit (Roche Diagnostics), etc.

[0017] The identity of nucleotide sequences can be determined using the algorithm BLAST (Basic Local Alignment Search Tool) by Carlin and Altschul (Proc. Natl. Acad. Sci. USA 872264-2268, 1990; Proc Natl Acad Sci USA 90: 5873, 1993). Programs called BLASTN and BLASTX based on the BLAST algorithm have been developed (Altschul SF, et al: J Mol Biol 215: 403, 1990). When analyzing nucleotide sequences using BLASTN, the parameters are, for example, score=100 and wordlength=12. When using the BLAST and Gapped BLAST programs, the default parameters of each program are used.

[0018] In one embodiment, the antisense oligonucleotides of the invention can be, for example, 15 or more nucleotides, 16 or more nucleotides, 17 or more nucleotides, 18 or more nucleotides, 19 or more nucleotides, 20 or more nucleotides, 21 or more nucleotides, 22 or more nucleotides, 23 or more nucleotides, 24 or more nucleotides, 25 or more nucleotides, 26 or more nucleotides, 27 or more nucleotides, 28 or more nucleotides, 29 or more nucleotides, or 30 nucleotides in length, or 30 or less nucleotides in length, 29 or less nucleotides in length, 28 or less nucleotides in length, 27 or less nucleotides in length, 26 or less nucleotides in length, 25 or less nucleotides in length, 24 or less nucleotides in length, 23 or less nucleotides in length, 22 or less nucleotides in length, 21 or less nucleotides in length, 20 or less nucleotides in length, 19 or less nucleotides in length, 18 or less nucleotides in length, 17 or less nucleotides in length, 16 or less nucleotides in length, or 15 nucleotides in length. The antisense oligonucleotide of the present invention may consist of, for example, 15 to 30 nucleotides, 15 to 25 nucleotides, 15 to 24 nucleotides, 15 to 23 nucleotides, 15 to 22 nucleotides, 15 to 21 nucleotides, 15 to 20 nucleotides, 16 to 25 nucleotides, 17 to 25 nucleotides, 18 to 25 nucleotides, 19 to 25 nucleotides, 20 to 25 nucleotides, 16 to 24 nucleotides, 17 to 23 nucleotides, 18 to 22 nucleotides, 19 to 21 nucleotides, or for example, 20 nucleotides.

[0019] Examples of pharma- ceutically acceptable salts of the antisense oligonucleotides of the present invention include alkali metal salts such as sodium salts, potassium salts, and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts; metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, and cobalt salts; ammonium salts; t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, triethylamine salts, dicyclohexylamine salts, N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine salts, diethanolamine salts, N-benzyl-phenethylamine salts, Examples of the salt include organic amine salts such as piperazine salt, tetramethylammonium salt, and tris(hydroxymethyl)aminomethane salt; hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonate salts such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate; arylsulfonate salts such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, and maleate; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate. These salts can be prepared by known methods. Alternatively, the antisense oligonucleotide of the present invention may be in the form of its hydrate. The antisense oligonucleotide of the present invention is composed of nucleotides as building blocks, and such nucleotides may be any of ribonucleotides, deoxyribonucleotides, or modified nucleotides.

[0020] A modified nucleotide refers to a ribonucleotide or deoxyribonucleotide in which the nucleic acid base, sugar moiety, and phosphate linkage moiety constituting the ribonucleotide or deoxyribonucleotide have been modified in whole or in part.

[0021] Examples of nucleic acid bases include adenine, guanine, hypoxanthine, cytosine, thymine, uracil, and modified bases thereof. Examples of such modified bases include pseudouracil, 3-methyluracil, dihydrouracil, 5-alkylcytosine (e.g., 5-methylcytosine), 5-alkyluracil (e.g., 5-ethyluracil), 5-halouracil (e.g., 5-bromouracil), 6-azapyrimidine, 6-alkylpyrimidine (e.g., 6-methyluracil), 2-thiouracil, 4-thiouracil, 4-acetylcytosine, 5-(carboxyhydroxymethyl)uracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-carboxymethylaminomethyluracil, 1-methyladenine, 1-methylhypoxanthine, 1-methyluracil ... Examples of such amino acids include, but are not limited to, xanthine, 2,2-dimethylguanine, 3-methylcytosine, 2-methyladenine, 2-methylguanine, N6-methyladenine, 7-methylguanine, 5-methoxyaminomethyl-2-thiouracil, 5-methylaminomethyluracil, 5-methylcarbonylmethyluracil, 5-methyloxyuracil, 5-methyl-2-thiouracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid, 2-thiocytosine, purine, 2,6-diaminopurine, 2-aminopurine, isoguanine, indole, imidazole, and xanthine.

[0022] In the present specification, thymine "T" and uracil "U" are mutually interchangeable, and since there is essentially no effect on the activity of the antisense oligonucleotide of the present invention whether it is "T" or "U", the base sequences shown in the present specification include the case where "T" is "U", and are shown with the same sequence number. Furthermore, in the present specification, a sequence containing a modified base is represented with the same sequence number as a sequence not containing a modified base, and for example, "cytosine" and "methylcytosine" are mutually interchangeable, and the case where "cytosine" is "methylcytosine" is also shown with the same sequence number.

[0023] Modification of the sugar moiety can include, for example, modification of the 2'-position of ribose and modification of other parts of the sugar. Modification of the 2'-position of ribose can include, for example, substitution of the -OH group at the 2'-position of ribose with -OR, -OROR, -R, -R'OR, -SH, -SR, -NH2, -NHR, -NR2, -N3, -CN, -F, -Cl, -Br, -I, such as -OMe (-O-CH3) or -O-methoxyethyl (-O-MOE: -O-CH2CH2OCH3). Here, R represents alkyl, cycloalkyl, acyl, or aryl. R' represents alkylene.

[0024] Modifications of other sugar moieties include, but are not limited to, for example, substitution of the O at the 4' position of ribose or deoxyribose with S, and bridging of the 2' and 4' positions of the sugar, such as LNA (Locked Nucleic Acid) or ENA (2'-O,4'-C-Ethylene-bridged Nucleic Acids).

[0025] Modifications of the phosphate linkage moiety include, for example, modifications in which the phosphodiester bond is replaced with a phosphorothioate bond, a phosphorodithioate bond, an alkylphosphonate bond, a phosphoramidate bond, or a boranophosphate bond (see, for example, Enya et al: Bioorganic & Medicinal Chemistry, 2008, 18, 9154-9160) (see, for example, Republished Patent Publication No. 2006 / 129594 and Republished Patent Publication No. 2006 / 038608).

[0026] In the present specification, the alkyl is preferably a linear or branched alkyl having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, and isohexyl. The alkyl may be substituted, and examples of such substituents include halogen, alkoxy, cyano, and nitro, and the alkyl may be substituted with 1 to 3 of these.

[0027] In this specification, the cycloalkyl is preferably a cycloalkyl having a carbon number of 3 to 12. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl.

[0028] In this specification, halogen can include fluorine, chlorine, bromine, and iodine.

[0029] In the present specification, examples of alkoxy include linear or branched alkoxy having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, etc. In particular, alkoxy having 1 to 3 carbon atoms is preferred.

[0030] In the present specification, the aryl is preferably an aryl having 6 to 10 carbon atoms. Specific examples include phenyl, α-naphthyl, and β-naphthyl. Phenyl is particularly preferred. The aryl may be substituted, and examples of such substituents include alkyl, halogen, alkoxy, cyano, and nitro, and 1 to 3 of these may be substituted.

[0031] In this specification, the alkylene is preferably a linear or branched alkylene having 1 to 6 carbon atoms. Specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 2-(ethyl)trimethylene, and 1-(methyl)tetramethylene.

[0032] In the present specification, acyl may include linear or branched alkanoyl or aroyl. Alkanoyl may include, for example, formyl, acetyl, 2-methylacetyl, 2,2-dimethylacetyl, propionyl, butyryl, isobutyryl, pentanoyl, 2,2-dimethylpropionyl, hexanoyl, etc. Aroyl may include, for example, benzoyl, toluoyl, naphthoyl. Such aroyl may be substituted at a substitutable position, or may be substituted with alkyl.

[0033] In one embodiment, the present invention provides a gapmer in which the antisense oligonucleotide comprises a central gap region and two wing regions (also referred to as 5' wing region and 3' wing region, respectively) flanking the 5' and 3' ends of the gap region. The gap region is a region recognized by RNase H and is composed of deoxyribonucleotides with unmodified sugar moieties. The wing regions comprise at least one modified nucleotide, for example, all of the wing regions are composed of modified nucleotides (e.g., ribonucleotides modified at the 2' position of the ribose). In one embodiment, the nucleosides in the 5' wing region and the 3' wing region each comprise at least one, for example, two or more, three or more, four or more, five or more sugar moiety modifications, for example, a 2'-OMe group and / or a 2'-O-MOE group, for example, all of the nucleosides in the 5' wing region and the 3' wing region may comprise a 2'-OMe group and / or a 2'-O-MOE group. Additionally, the nucleosides of the 5' and 3' wing regions may contain modifications at the base moiety, such as at least one methylcytosine.

[0034] The length of the gap region is not limited, but may be, for example, 5 to 15, 8 to 12, 9 to 11, or 10 bases long. The lengths of the 5' wing region and the 3' wing region are not limited, but may be, for example, each independently, 2 to 10, 3 to 8, 4 to 6, or 5 bases long. In one embodiment, the gap region is 10 bases long, and the 5' wing region and the 3' wing region are each 5 bases long.

[0035] In one embodiment, a gapmer of the invention comprises one or more phosphate linkage modifications, such as phosphorothioate linkages, for example, one or more, two or more, three or more, four or more, five or more, ten or more, fifteen or more, e.g., all, of the internucleoside linkages may be phosphorothioate linkages. In one embodiment, a gapmer of the invention comprises all phosphorothioate linkages between nucleosides. In one embodiment, a gapmer of the invention comprises one or more, two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, or ten or more (e.g., two to six) phosphodiester linkages, for example in the 5' wing region and / or the 3' wing region, and all other internucleoside linkages are phosphorothioate linkages. In one embodiment, one or more of the bonds between the second and third nucleosides from the 5' side, the bond between the third and fourth nucleosides, and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or one or more of the bonds between the first and second nucleosides from the 5' side, the bond between the second and third nucleosides, and the bond between the third and fourth nucleosides from the 5' side of the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds. In one embodiment, the bonds between the second and third nucleosides from the 5' side and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or the bonds between the first and second nucleosides from the 5' side and the third and fourth nucleosides from the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds. In one embodiment, the bond between the second and third nucleosides, the bond between the third and fourth nucleosides, and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or the bond between the first and second nucleosides, the bond between the second and third nucleosides, and the bond between the third and fourth nucleosides from the 5' side of the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds.In one embodiment, the bond between the second and third nucleosides from the 5' side and the bond between the third and fourth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or the bond between the second and third nucleosides from the 5' side and the bond between the third and fourth nucleosides from the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds. In one embodiment, the bond between the third and fourth nucleosides from the 5' side and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or the bond between the first and second nucleosides from the 5' side and the bond between the second and third nucleosides from the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds. In one embodiment, the bond between the second and third nucleosides from the 5' side of the 5' wing region is a phosphodiester bond, and / or the bond between the third and fourth nucleosides from the 5' side of the 3' wing region is a phosphodiester bond, and all other internucleoside bonds are phosphorothioate bonds. In one embodiment, the bond between the third and fourth nucleosides from the 5' side of the 5' wing region is a phosphodiester bond, and / or the bond between the second and third nucleosides from the 5' side of the 3' wing region is a phosphodiester bond, and all other internucleoside bonds are phosphorothioate bonds. In one embodiment, the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region is a phosphodiester bond, and / or the bond between the first and second nucleosides from the 5' side of the 3' wing region is a phosphodiester bond, and all other internucleoside bonds are phosphorothioate bonds. In one embodiment, a gapmer of the invention does not contain modifications at the phosphate linkages and all of the internucleotide linkages may be phosphodiester linkages.

[0036] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 1 to 84, 142 to 168, 197 to 224, 286 to 317, 324 to 370, 391 to 434, 519 to 540, 623 to 643, 690 to 780, 824 to 855, 860 to 897, 948 to 987, and 950 to 951 of the base sequence of SEQ ID NO:471. 1044th to 1072nd, 1125th to 1174th, 1181st to 1213th, 1228th to 1255th, 1265th to 1327th, 1334th to 1356th, 1416th to 1440th, 1447th to 1631st, 1638th to 1667th, 1675th to 1705th, 1748th to 1823rd, 1838th to 1861st, 1870th to 1913th, 19 20th~1941st, 2000~2040, 2047~2075, 2086~2120, 2129~2187, 2194~2415, 2451~2497 2592nd ~ 2759th, 2766th ~ 2870th, 2928th ~ 2948th, 2955th ~ 2989th, 3021st ~ 3086th, 3133rd ~ 3209th, 3217th ~ It is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 3284, 3295 to 3350, 3384 to 3436, 3562 to 3771, 3858 to 3905, 3931 to 4039, 4067 to 4134, 4170 to 4232, 4241 to 4283, and 4286 to 4355.

[0037] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 1 to 84, 142 to 168, 391 to 434, 697 to 780, 962 to 980, 1125 to 1174, 1181 to 1213, 1228 to 1255, 1265 to 1320, 1454 to 1631, 1682 to 1705, 1748 to 1816, 1870 to 1913, 2015 to 2040, 2086 to 2120, 2129 to 2221, 2230 to 2232, 2233 to 2234, 2235 to 2236, 2237 to 2238, 2239 to 2240, 2241 to 2242, 2243 to 2244, 2245 to 2250, 2246 to 2252, 2247 to 2256, 2248 to 2250, 2249 to 2261, 2251 to 2262, 2252 to 2263, 2253 to 2264, 2254 to 2276, 2255 to 2278, 2256 to 2290, 2257 to 2291, 2259 to 2300, 2301 to 2302, 2303 to 2304, 2305 to 2306, 2307 to 2308, 2309 to 2409, 2410 to 2421 It is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 187, 2201-2408, 2592-2759, 2773-2870, 2955-2982, 3028-3079, 3133-3209, 3224-3277, 3295-3350, 3391-3429, 3562-3771, 3865-3898, 3938-4032, 4074-4127, and 4170-4225.

[0038] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 1 to 69, 331 to 363, 398 to 427, 697 to 773, 867 to 890, 955 to 980, 1132 to 1167, 1272 to 1320, 1454 to 1624, 1682 to 1705, 1748 to 1816, 1877 to 1906, 2007 to 2033, 2093 to 2113, 2136 to 2180, 2201 to 2408, 2458 to 2506, 2509 to 2601, 2602 to 2703, 2704 to 2705, 2706 to 2710, 2708 to 2711, 2709 to 2806, 2807 to 2810, 2811 to 2812, 2813 to 2814, 2815 to 2816, 2820 to 2822, 2821 to 2824, 2822 to 2826, 2823 to 2828, 2824 to 2829, 2830 to 2840, 2831 to 2842, 2832 to 2846, 2833 to 2848, 2836 to 2844, 2835 to 2846, 2836 to 2848, 2837 to 2849, 2849 to 2850, 2851 to 2852, It is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 90, 2599-2752, 2773-2863, 2962-2982, 3028-3079, 3140-3202, 3224-3277, 3302-3343, 3391-3429, 3569-3764, 3865-3898, 3938-4032, 4074-4127, 4177-4225, 4248-4276, and 4293-4355.

[0039] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 1 to 69, 398 to 427, 697 to 773, 1132 to 1167, 1272 to 1320, 1454 to 1624, 1682 to 1705, 1748 to 1816, 1877 to 1906, 2093 to 2113, 2136 to 2180, 2201 to 2408, and 2599 of the base sequence of SEQ ID NO:471. It is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 2752, 2773 to 2863, 2962 to 2982, 3028 to 3079, 3140 to 3202, 3224 to 3277, 3302 to 3343, 3391 to 3429, 3569 to 3764, 3865 to 3898, 3938 to 4032, and 4177 to 4225.

[0040] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 432, 723 to 742, 747 to 778, 965 to 984, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1228 to 1230, 1232 to 1234, 1236 to 1238, 1239 to 1241, 1242 to 1245, 1246 to 1248, 1248 to 1250, 1249 to 1251, 1252 to 1253, 1254 to 1255, 1256 to 1260, 1262 to 1263, 1264 to 1265, 1266 to 1267, 1270 to 1270, 1272 to 1271, 1274 to 1275, 1276 to 1277, 1278 to 1279, 1280 to 1281, 1282 to 1284, 1286 to 1285, 1288 to 1286, 1288 to 1289, 1290 to 1300, 1304 to 1306, 1308 to 1310, 1312 to 1313, 1314 to 1315, 1316 to 1317, 1318 to 1319, 1320 to 1 ~1254th, 1270~1308, 1484~1564, 1578~1629, 1686~1705, 1748~1767, 1768~1787 , 1794th ~ 1813th, 1870th ~ 1913th, 2015th ~ 2034th, 2086th ~ 2118th, 2129th ~ 2148th, 2151st ~ 2184th, 2206th ~ 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2598th to 2757th, 2775th to 2809th, 2 826th to 2866th, 2959th to 2982nd, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3155th, 3168th to 3187th, 3188th to 32nd 07, 3232-3270, 3298-3344, 3408-3427, 3563-3582, 3590-3728, 3739-3769, 3877-3896, 3949-4030, and 4170-4225. In one embodiment, the antisense oligonucleotide of the present invention is located at positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 416, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 422, 404 to 423, 405 to 424, 406 to 425, 407 to 426, 408 to 427, 413 to 432, 723 to 742, 747 to 766, 756 to 775, 759 to 778, 965 to 984, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1173, 1182 to 1201, 1185 to 1204, 1188 to 1207, 1191 to 1210, 1194 to 1213, 1228 to 1247, 1231 to 1250, 1235 to 1254, 1270 to 1289, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1506 to 1525, 1517 to 1536, 1531 to 1550, 1545 to 1564, 1578 to 1597, 1579 to 1598, 1580 to 1599, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1586 to 1605, 1587 to 1606, 1588 to 1607, 1589 to 1608, 1590 to 1609, 1591 to 1610, 1592 to 1611, 1593 to 1612, 1594 to 1613, 1595 to 1614, 1596 to 1615, 1597 to 1616, 1598 to 1617, 1599 to 1618, 1600 to 1619, 1601 to 1620, 1602 to 1621, 1603 to 1622, 1604 to 1623, 1605 to 1624, 1607 to 1626, 1610 to 1629, 1686 to 1705, 1748 to 1767, 1768 to 1787, 1794 to 1813, 1870 to 1889, 1871 to 1890, 1874 to 1893, 1877 to 1896, 1878 to 1897 of the nucleotide sequence of SEQ ID NO: 471.1879~1898, 1880~1899, 1881~1900, 1882~1901, 1883~1902, 1884~1903, 1885~1904, 1886~1905, 1887~1906, 1889~1908, 1894 1913, 2015-2034, 2086-2105, 2093-2112, 2094-2113, 2097-2116, 2099-2118, 2129-2148, 2151-2170, 2165-2184, 2206-222 5, 2239-2258, 2253-2272, 2287-2306, 2301-2320, 2317-2336, 2337-2356, 2354-2373, 2387-2406, 2598-2617, 2613-2632, 2 614~2633, 2615~2634, 2616~2635, 2617~2636, 2618~2637, 2619~2638, 2620~2639, 2621~2640, 2622~2641, 2623~2642, 2624~ 2643, 2625~2644, 2626~2645, 2627~2646, 2628~2647, 2629~2648, 2630~2649, 2631~2650, 2632~2651, 2633~2652, 2634~2653 2635~2654, 2636~2655, 2637~2656, 2638~2657, 2639~2658, 2640~2659, 2641~2660, 2642~2661, 2643~2662, 2644~2663, 264 5~2664, 2646~2665, 2647~2666, 2648~2667, 2649~2668, 2663~2682, 2672~2691, 2673~2692, 2674~2693, 2675~2694, 2676~2 695, 2677~2696, 2678~2697, 2679~2698, 2680~2699, 2681~2700, 2682~2701, 2683~2702, 2684~2703, 2685~2704, 2686~2705,2687~2706, 2688~2707, 2689~2708, 2690~2709, 2691~2710, 2692~2711, 2693~2712, 2694~2713, 2695~2714, 2696~2715, 2697 2701~2720, 2702~2721, 2703~2722, 2704~2723, 2705~2724, 2706~2725, 2707~272 6, 2708~2727, 2709~2728, 2710~2729, 2711~2730, 2712~2731, 2713~2732, 2714~2733, 2715~2734, 2716~2735, 2717~2736, 2 718~2737, 2719~2738, 2720~2739, 2721~2740, 2722~2741, 2723~2742, 2724~2743, 2725~2744, 2726~2745, 2727~2746, 2728~ 2747, 2729~2748, 2730~2749, 2731~2750, 2732~2751, 2733~2752, 2738~2757, 2775~2794, 2790~2809, 2826~2845, 2827~2846 2828~2847, 2829~2848, 2830~2849, 2831~2850, 2832~2851, 2833~2852, 2834~2853, 2835~2854, 2836~2855, 2837~2856, 283 8~2857, 2839~2858, 2840~2859, 2841~2860, 2842~2861, 2843~2862, 2844~2863, 2847~2866, 2959~2978, 2962~2981, 2963~2 982, 3032~3051, 3052~3071, 3136~3155, 3168~3187, 3188~3207, 3232~3251, 3251~3270, 3298~3317, 3302~3321, 3303~3322,3304~3323, 3305~3324, 3306~3325, 3307~3326, 3308~3327, 3309~3328, 3310~3329, 3311~3330, 3312~3331, 3313~3332, 3314 3320~3329, 3321~3340, 3322~3341, 3323~3342, 3324~3343 3, 3325~3344, 3408~3427, 3563~3582, 3590~3609, 3608~3627, 3617~3636, 3618~3637, 3619~3638, 3620~3639, 3621~3640, 3 622~3641, 3623~3642, 3624~3643, 3625~3644, 3626~3645, 3627~3646, 3628~3647, 3629~3648, 3630~3649, 3631~3650, 3632~ 3651, 3633~3652, 3634~3653, 3635~3654, 3636~3655, 3637~3656, 3638~3657, 3639~3658, 3640~3659, 3641~3660, 3642~3661 , 3643~3662, 3644~3663, 3645~3664, 3646~3665, 3647~3666, 3648~3667, 3649~3668, 3650~3669, 3651~3670, 3652~3671, 365 3rd to 3672nd, 3654th to 3673rd, 3671st to 3690th, 3672nd to 3691st, 3673rd to 3692nd, 3674th to 3693rd, 3675th to 3694th, 3676th to 3695th, 3677th to 3696th, 3678th to 3697th, 3679th to 3 698, 3680~3699, 3681~3700, 3682~3701, 3683~3702, 3684~3703, 3685~3704, 3686~3705, 3687~3706, 3688~3707, 3689~3708,3690~3709, 3691~3710, 3692~3711, 3693~3712, 3694~3713, 3695~3714, 3696~3715, 3697~3716, 3698~3717, 3699~3718, 3700 3701~3720, 3702~3721, 3703~3722, 3704~3723, 3705~3724, 3706~3725, 3707~3726, 3708~3727, 3709~3728, 3739~3750 8, 3740~3759, 3741~3760, 3742~3761, 3743~3762, 3744~3763, 3745~3764, 3750~3769, 3877~3896, 3949~3968, 3964~3983, 3 965~3984, 3966~3985, 3967~3986, 3968~3987, 3969~3988, 3970~3989, 3971~3990, 3972~3991, 3973~3992, 3974~3993, 3975~ 3994, 3976~3995, 3977~3996, 3978~3997, 3979~3998, 3980~3999, 3981~4000, 3982~4001, 3983~4002, 3984~4003, 3985~4004 3986~4005, 3987~4006, 3988~4007, 3989~4008, 3990~4009, 3991~4010, 3992~4011, 3993~4012, 3994~4013, 3995~4014, 399 6~4015, 3997~4016, 3998~4017, 3999~4018, 4011~4030, 4170~4189, 4173~4192, 4176~4195, 4177~4196, 4178~4197, 4179~4 198, 4180~4199, 4181~4200, 4182~4201, 4183~4202, 4184~4203, 4185~4204, 4186~4205, 4187~4206, 4188~4207, 4189~4208,It is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 4190 to 4209, 4191 to 4210, 4192 to 4211, 4193 to 4212, 4194 to 4213, 4195 to 4214, 4196 to 4215, 4197 to 4216, 4198 to 4217, 4199 to 4218, 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224, and 4206 to 4225.

[0041] Examples of antisense oligonucleotides that are complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464, in which one or several bases have been added, deleted, or substituted; or (iii) a base sequence having 90% or more sequence identity to a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464; For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0042] In this specification, in a base sequence in which one or several bases have been added, deleted or substituted, the term "several" means 2, 3, 4, 5, 6, 7, 8, 9, or 10 bases.

[0043] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 14 to 33, 34 to 53, 398 to 427, 723 to 742, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1564, 1578 to 1624, 1686 to 1705, 1748 to 1767, 1768 to 1787, 1794 to 1813, 1877 to 1906, 2093 to 2113, 2151 to 2170, 2206 to 2225, 2239 to 2272, 2287 to 2313, 2289 to 2314, 2289 to 2315, 2289 to 2316, 2289 to 2318, 2289 to 2319, 2290 to 2320, 2291 to 2322, 2292 to 2324, 2300 to 2302, 2302 to 2326, 2304 to 2328, 2306 to 2329, 2308 to 2329, 2400 to 2402, 2404 to 2406, 2406 to 2408, 2408 to 2409, 2500 to 2506, 2500 to 2509, 2600 to 2607, 2600 to 2609, 2700 to 2706, 2700 to 2709, It is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 36, 2337 to 2373, 2387 to 2406, 2613 to 2752, 2775 to 2809, 2826 to 2863, 2962 to 2982, 3032 to 3051, 3052 to 3071, 3168 to 3187, 3232 to 3270, 3302 to 3343, 3408 to 3427, 3590 to 3728, 3739 to 3764, 3877 to 3896, 3949 to 4030, and 4177 to 4225.

[0044] In one embodiment, the antisense oligonucleotide of the present invention is located at positions 14 to 33, 34 to 53, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 422, 404 to 423, 405 to 424, 406 to 425, 407 to 426, 408 to 427, 723 to 742, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1506 to 1525, 1517 to 1536, 1531 to 1550, 1545 to 1564, 1578 to 1597, 1579 to 1598, 1580 to 1599, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1586 to 1605, 1587 to 1606, 1588 to 1607, 1589 to 1608, 1590 to 1609, 1591 to 1610, 1592 to 1611, 1593 to 1612, 1594 to 1613, 1595 to 1614, 1596 to 1615, 1597 to 1616, 1598 to 1617, 1599 to 1618, 1600 to 1619, 1601 to 1620, 1602 to 1621, 1603 to 1622, 1604 to 1623, 1605 to 1624, 1686 to 1705, 1748 to 1767, 1768 to 1787, 1794 to 1813, 1877 to 1896, 1878 to 1897, 1879 to 1898, 1880 to 1899, 1881 to 1900, 1882 to 1901, 1883 to 1902, 1884 to 1903, 1885 to 1904, 1886 to 1905, 1887 to 1906, 2093 to 2112, 2094 to 2113, 2151 to 2170, 2206 to 2225, 2239 to 2258, 2253 to 2272, 2287 to 2306, 2301 to 2320, 2317 to 2336, 2337 to 2356, 2354 to 2373, 2387 to 2406, 2613 to 2632, 2614 to 2633 of the nucleotide sequence of SEQ ID NO: 471.2615~2634, 2616~2635, 2617~2636, 2618~2637, 2619~2638, 2620~2639, 2621~2640, 2622~2641, 2623~2642, 2624~2643, 2625 2626~2645, 2627~2646, 2628~2647, 2629~2648, 2630~2649, 2631~2650, 2632~2651, 2633~2652, 2634~2653, 2635~265 4, 2636~2655, 2637~2656, 2638~2657, 2639~2658, 2640~2659, 2641~2660, 2642~2661, 2643~2662, 2644~2663, 2645~2664, 2 646~2665, 2647~2666, 2648~2667, 2649~2668, 2663~2682, 2672~2691, 2673~2692, 2674~2693, 2675~2694, 2676~2695, 2677~ 2696, 2678~2697, 2679~2698, 2680~2699, 2681~2700, 2682~2701, 2683~2702, 2684~2703, 2685~2704, 2686~2705, 2687~2706 2688~2707, 2689~2708, 2690~2709, 2691~2710, 2692~2711, 2693~2712, 2694~2713, 2695~2714, 2696~2715, 2697~2716, 269 8~2717, 2699~2718, 2700~2719, 2701~2720, 2702~2721, 2703~2722, 2704~2723, 2705~2724, 2706~2725, 2707~2726, 2708~2 727, 2709-2728, 2710-2729, 2711-2730, 2712-2731, 2713-2732, 2714-2733, 2715-2734, 2716-2735, 2717-2736, 2718-2737,2719~2738, 2720~2739, 2721~2740, 2722~2741, 2723~2742, 2724~2743, 2725~2744, 2726~2745, 2727~2746, 2728~2747, 2729 2748, 2730-2749, 2731-2750, 2732-2751, 2733-2752, 2775-2794, 2790-2809, 2826-2845, 2827-2846, 2828-2847, 2829-284 8, 2830~2849, 2831~2850, 2832~2851, 2833~2852, 2834~2853, 2835~2854, 2836~2855, 2837~2856, 2838~2857, 2839~2858, 2 840~2859, 2841~2860, 2842~2861, 2843~2862, 2844~2863, 2962~2981, 2963~2982, 3032~3051, 3052~3071, 3168~3187, 3232~ 3251, 3251~3270, 3302~3321, 3303~3322, 3304~3323, 3305~3324, 3306~3325, 3307~3326, 3308~3327, 3309~3328, 3310~3329 , 3311~3330, 3312~3331, 3313~3332, 3314~3333, 3315~3334, 3316~3335, 3317~3336, 3318~3337, 3319~3338, 3320~3339, 332 1~3340, 3322~3341, 3323~3342, 3324~3343, 3408~3427, 3590~3609, 3608~3627, 3617~3636, 3618~3637, 3619~3638, 3620~3 639, 3621~3640, 3622~3641, 3623~3642, 3624~3643, 3625~3644, 3626~3645, 3627~3646, 3628~3647, 3629~3648, 3630~3649,3631~3650, 3632~3651, 3633~3652, 3634~3653, 3635~3654, 3636~3655, 3637~3656, 3638~3657, 3639~3658, 3640~3659, 3641 ~3660, 3642~3661, 3643~3662, 3644~3663, 3645~3664, 3646~3665, 3647~3666, 3648~3667, 3649~3668, 3650~3669, 3651~367 0, 3652~3671, 3653~3672, 3654~3673, 3671~3690, 3672~3691, 3673~3692, 3674~3693, 3675~3694, 3676~3695, 3677~3696, 3 678~3697, 3679~3698, 3680~3699, 3681~3700, 3682~3701, 3683~3702, 3684~3703, 3685~3704, 3686~3705, 3687~3706, 3688~ 3707, 3689~3708, 3690~3709, 3691~3710, 3692~3711, 3693~3712, 3694~3713, 3695~3714, 3696~3715, 3697~3716, 3698~3717 3699~3718, 3700~3719, 3701~3720, 3702~3721, 3703~3722, 3704~3723, 3705~3724, 3706~3725, 3707~3726, 3708~3727, 3709~3710 9th to 3728th, 3739th to 3758th, 3740th to 3759th, 3741st to 3760th, 3742nd to 3761st, 3743rd to 3762nd, 3744th to 3763rd, 3745th to 3764th, 3877th to 3896th, 3949th to 3968th, 3964th to 3 983rd, 3965th to 3984th, 3966th to 3985th, 3967th to 3986th, 3968th to 3987th, 3969th to 3988th, 3970th to 3989th, 3971st to 3990th, 3972nd to 3991st, 3973rd to 3992nd, 3974th to 3993rd,3975th to 3994th, 3976th to 3995th, 3977th to 3996th, 3978th ​​to 3997th, 3979th to 3998th, 3980th to 3999th, 3981st to 4000th, 3982nd ~4001st, 3983rd ~ 4002nd, 3984th ~ 4003rd, 3985th ~ 4004th, 3986th ~ 4005th, 3987th ~ 4006th, 3988th ~ 4007th, 3989th ~ 4008th , 3990th to 4009th, 3991st to 4010th, 3992nd to 4011th, 3993rd to 4012th, 3994th to 4013th, 3995th to 4014th, 3996th to 4015th, 3997th ~4016th, 3998th ~ 4017th, 3999th ~ 4018th, 4011th ~ 4030th, 4177th ~ 4196th, 4178th ~ 4197th, 4179th ~ 4198th, 4180th ~ 4199th , 4181st to 4200th, 4182nd to 4201st, 4183rd to 4202nd, 4184th to 4203rd, 4185th to 4204th, 4186th to 4205th, 4187th to 4206th, 4188 ~4207th, 4189~4208, 4190~4209, 4191~4210, 4192~4211, 4193~4212, 4194~4213, 4195~4214 positions, 4196 to 4215, 4197 to 4216, 4198 to 4217, 4199 to 4218, 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224, and 4206 to 4225.

[0045] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163 to 464; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163 to 464, in which one or several bases have been added, deleted, or substituted; or (iii) a base sequence having 90% or more sequence identity to a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14 to 24, 31 to 35, 37 to 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163 to 464; For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0046] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 432, 747 to 778, 965 to 984, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1228 to 1254, 1270 to 1308, 1470 to 1492, 1470 to 1506, 1508 to 1510, 1512 to 1514, 1516 to 1518, 1519 to 1520, 1521 to 1522, 1523 to 1524, 1525 to 1526, 1527 to 1528, 1529 to 1530, 1531 to 1532, 1534 to 1536, 1538 to 1538, 1539 to 1540, 1541 to 1542, 1543 to 1544, 1545 to 1546, 1547 to 1548, 1549 to 1550, 1551 to 1552, 1552 to 1556, 1553 to 1558, 1556 to 1550, 1551 to 1552, 1553 to 1556, 1557 to 1559, 1560 to 1561, 1562 to 1563, 1564 to 1565, 1566 to 84th to 1564th, 1578th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1913th, 201 5th ~ 2034th, 2086 ~ 2118th, 2129th ~ 2148th, 2151st ~ 2170th, 2206th ~ 2225th, 2239th ~ 2272nd, 2287th ~ 2336th, 2337th ~2373rd, 2387th ~ 2406th, 2598th ~ 2632nd, 2633rd ~ 2668th, 2672nd ~ 2691st, 2699th ~ 2757th, 2775th ~ 2809th, 2826th ~ 2866th, 2959th - 2978th, 3032nd - 3051st, 3052nd - 3071st, 3136th - 3155th, 3168th - 3187th, 3188th - 3207th, 3232nd - 3 It is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 270, 3298 to 3317, 3325 to 3344, 3408 to 3427, 3590 to 3690, 3691 to 3728, 3739 to 3769, 3877 to 3896, 3949 to 3983, 3984 to 4030, and 4170 to 4198.

[0047] In one embodiment, the antisense oligonucleotide of the present invention is located at positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 416, 413 to 432, 747 to 766, 756 to 775, 759 to 778, 965 to 984, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1173, 1182 to 1201, 1185 to 1204, 1188 to 1207, 1191 to 1210, 1194 to 1213, 1228 to 1247, 1231 to 1250, 1235 to 1254, 1270 to 1289, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1506 to 1525, 1517 to 1536, 1531 to 1550, 1545 to 1564, 1578 to 1597, 1586 to 1605, 1589 to 1608, 1592 to 1611, 1595 to 1614, 1598 to 1617, 1601 to 1620, 1604 to 1623, 1607 to 1626, 1610 to 1629, 1686 to 1705, 1748 to 1767, 1768 to 1787, 1794 to 1813, 1870 to 1889, 1871 to 1890, 1874 to 1893, 1877 to 1896, 1880 to 1899, 1883 to 1902, 1886 to 1905, 1889 to 1908, 1894 to 1913, 2015 to 2034, 2086 to 2105, 2097 to 2116, 2099 to 2118, 2129 to 2148, 2151 to 2170, 2206 to 2225, 2239 to 2258, 2253 to 2272, 2287 to 2306, 2301 to 2320, 2317 to 2336, 2337 to 2356, 2354 to 2373, 2387 to 2406, 2598 to 2617, 2613 to 2632, 2633 to 2652, 2649 to 2668, 2672 to 2691, 2699 to 2718, 2702 to 2721, 2705 to 2724, 2708 to 2727, 2711 to 2730, 2714 to 2733 of the nucleotide sequence of SEQ ID NO: 471.2717th to 2736th, 2720th to 2739th, 2723rd to 2742nd, 2726th to 2745th, 2729th to 2748th, 2738th to 2757th, 27 75th to 2794th, 2790th to 2809th, 2826th to 2845th, 2829th to 2848th, 2832nd to 2851st, 2835th to 2854th, 2838th ~2857th, 2841st ~ 2860th, 2847th ~ 2866th, 2959th ~ 2978th, 3032nd ~ 3051st, 3052nd ~ 3071st, 3136th ~ 31st 55th, 3168th to 3187th, 3188th to 3207th, 3232nd to 3251st, 3251st to 3270th, 3298th to 3317th, 3325th to 3344th , 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3635th to 3654th, 3654th to 3673rd, 3 671st to 3690th, 3691st to 3710th, 3709th to 3728th, 3739th to 3758th, 3750th to 3769th, 3877th to 3896th, 3949th It is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 3968 to 3968, 3964 to 3983, 3984 to 4003, 3999 to 4018, 4011 to 4030, 4170 to 4189, 4173 to 4192, 4176 to 4195, and 4179 to 4198.

[0048] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163, in which one or several bases have been added, deleted, or substituted; or (iii) a base sequence having 90% or more sequence identity to a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163; For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0049] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 14 to 33, 34 to 53, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1564, 1578 to 1623, 1686 to 1705, 1748 to 1767, 1768 to 1787, 1794 to 1813, 1877 to 1905, 2151 to 2170, 2206 to 2225, 2239 to 2272, 2287 to 2336, 2337 to 2373, 2387 to 2406, 2613 to 2625, 2716 to 2718, 2719 to 2816, 2820 to 2825, 2821 to 2826, 2822 to 2828, 2823 to 2829, 2824 to 2829, 2825 to 2829, 2826 to 2830, 2830 to 2831, 2831 to 2832, 2832 to 2833, 2833 to 2834, 2834 to 2835, 2835 to 2836, 2835 to 2837, 2836 to 2838, 2837 to 2839, 2838 to 2840, 2840 to 2842, 2839 to 2843, 2839 to 2844, 2839 to 2 It is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 2632, 2633 to 2668, 2672 to 2691, 2699 to 2748, 2775 to 2809, 2826 to 2860, 3032 to 3051, 3052 to 3071, 3168 to 3187, 3232 to 3270, 3408 to 3427, 3590 to 3690, 3691 to 3728, 3739 to 3758, 3877 to 3896, 3949 to 3983, 3984 to 4030, and 4179 to 4198.

[0050] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 14 to 33, 34 to 53, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1506 to 1525, 1517 to 1536, 1531 to 1550, 1545 to 1564, 1578 to 1597, 1586 to 1605, 1589 to 1608, 1592 to 1611, and 1595 to 1614 of the base sequence of SEQ ID NO:471. 1598th to 1617th, 1601st to 1620th, 1604th to 1623rd, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1896th, 1880th to 1899th, 1883rd to 1902nd, 18 86th to 1905th, 2151st to 2170th, 2206th to 2225th, 2239th to 2258th, 2253rd to 2272nd, 2287 2306th ~ 2306th, 2301st ~ 2320th, 2317th ~ 2336th, 2337th ~ 2356th, 2354th ~ 2373rd, 2387th ~ 2 406th place, 2613th ~ 2632nd, 2633rd ~ 2652nd, 2649th ~ 2668th, 2672nd ~ 2691st, 2699th ~ 271st 8th place, 2702nd ~ 2721st, 2705th ~ 2724th, 2708th ~ 2727th, 2711th ~ 2730th, 2714th ~ 2733rd , 2717th to 2736th, 2720th to 2739th, 2723rd to 2742nd, 2726th to 2745th, 2729th to 2748th, 2 775th to 2794th, 2790th to 2809th, 2826th to 2845th, 2829th to 2848th, 2832nd to 2851st, 283 5th to 2854th, 2838th to 2857th, 2841st to 2860th, 3032nd to 3051st, 3052nd to 3071st, 3168th ~3187th, 3232nd ~ 3251st, 3251st ~ 3270th, 3408th ~ 3427th, 3590th ~ 3609th, 3608th ~ 3 627th, 3617th to 3636th, 3635th to 3654th, 3654th to 3673rd, 3671st to 3690th, 3691st to 371th 0th place, 3709th to 3728th, 3739th to 3758th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd,It is complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 3984 to 4003, positions 3999 to 4018, positions 4011 to 4030, and positions 4179 to 4198.

[0051] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163, in which one or several bases have been added, deleted, or substituted; or (iii) a base sequence having 90% or more sequence identity to a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14 to 24, 31 to 35, 37, 39, 40, 42 to 45, 47 to 50, 52 to 59, 73, 92 to 100, 103, 107 to 110, 120 to 136, 138 to 143, 150 to 153, 155 to 158, and 163; For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0052] In one embodiment, the antisense oligonucleotide of the present invention is selected from those in which, when measured according to the method described in the Examples of the present specification, the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells to the ATN-1 gene expression level when administered with the positive control antisense oligonucleotides OMe-6 or NRH-71 is 1.0 or less in any of the Examples. Examples of such antisense oligonucleotides include those targeted to the base sequence of SEQ ID NO:471 at positions 397 to 416, 759 to 778, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1488 to 1525, 1586 to 1629, 1686 to 1705, 1768 to 1787, 1870 to 1908, 2097 to 2118, 2151 to 2170, 2239 to 2258, 2287 to 2306, 2317 to 2336, and antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 2633 to 2652, 2702 to 2745, 2832 to 2866, 2959 to 2978, 3298 to 3317, 3635 to 3654, 3671 to 3690, 3691 to 3710, 3750 to 3983, 3984 to 4003, and 4170 to 4198.In addition, positions 397 to 416, 759 to 778, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1173, 1182 to 1201, 1185 to 1204, 1194 to 1213, 1488 to 1507, 1491 to 1510, 1506 to 1525, 1586 to 1605, 1589 to 1608, 1595 to 1614, 1598 to 1619, 1599 to 1620, 1621 to 1622, 1623 to 1624, 1625 to 1626, 1627 to 1628, 1629 to 1630, 1631 to 1632, 1633 to 1634, 1635 to 1636, 1637 to 1638, 1639 to 1640, 1641 to 1642, 1643 to 1644, 1645 to 1646, 1647 to 1648, 1649 to 1650, 1651 to 1652, 1653 to 1654, 1655 to 1656, 1657 to 1658, 1659 to 1660, 1661 to 1662, 1663 to 1664, 1665 to 1666, 1667 to 1670, 1671 to 1672, 1673 to 17th, 1601st to 1620th, 1604th to 1623rd, 1607th to 1626th, 1610th to 1629th, 1686th to 1705th, 1768th to 1787th, 1870th to 1889th, 1871st to 1890th, 1874th to 1893rd, 1877th to 1896th, 1886th to 1905th, 1889th to 1908th, 2097th to 2116th, 2099th to 2118th, 2151st to 2170th, 2239th to 2258th, 2287th ~2306th, 2317th ~ 2336th, 2633rd ~ 2652nd, 2702nd ~ 2721st, 2705th ~ 2724th, 2708th ~ 2727th, 2711th ~ 2730th, 2714th ~ 2733rd, 2717th ~ 273th 6th place, 2720th to 2739th, 2726th to 2745th, 2832nd to 2851st, 2835th to 2854th, 2841st to 2860th, 2847th to 2866th, 2959th to 2978th, 3298th to 3317th, 36 and antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 35 to 3654, 3671 to 3690, 3691 to 3710, 3750 to 3769, 3964 to 3983, 3984 to 4003, 4170 to 4189, 4173 to 4192, 4176 to 4195, and 4179 to 4198.

[0053] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157, and 160 to 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157, and 160 to 163, in which one or several bases have been added, deleted, or substituted; or (iii) a base sequence having 90% or more sequence identity to a base sequence selected from the group consisting of SEQ ID NOs: 9, 11, 16, 17, 22, 31, 60, 67, 73, 74, 75, 79, 80, 92, 95 to 107, 110, 111, 116, 117, 120 to 122, 126, 128 to 134, 136, 140, 141, 143 to 145, 148, 151 to 154, 156, 157, and 160 to 163; For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0054] In one embodiment, the antisense oligonucleotide of the present invention is selected from those in which, when measured according to the method described in the Examples of the present specification, the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells to the ATN-1 gene expression level when administered with the positive control antisense oligonucleotides OMe-6 or NRH-71 is 0.75 or less in any of the Examples. Examples of such antisense oligonucleotides include antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 397 to 416, 1194 to 1213, 1506 to 1525, 1586 to 1626, 1870 to 1896, 2097 to 2116, 2317 to 2336, 2633 to 2652, 2702 to 2739, 2841 to 2978, 3298 to 3317, 3635 to 3654, 3691 to 3710, 3750 to 3769, 3984 to 4003, and 4170 to 4198 of the base sequence of SEQ ID NO: 471. In addition, positions 397 to 416, 1194 to 1213, 1506 to 1525, 1586 to 1605, 1595 to 1614, 1598 to 1617, 1604 to 1623, 1607 to 1626, 1870 to 1889, 1871 to 1890, 1874 to 1893, 1877 to 1896, 2097 to 2116, 2317 to 2336, 2633 to 2652, 2702 to 2721, 2708 to 2727, 2711 to 2730, 2714 to 2733, and antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 2717 to 2736, 2720 to 2739, 2841 to 2860, 2959 to 2978, 3298 to 3317, 3635 to 3654, 3691 to 3710, 3750 to 3769, 3984 to 4003, 4170 to 4189, 4173 to 4192, 4176 to 4195, and 4179 to 4198.

[0055] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157, and 160 to 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157, and 160 to 163, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 60, 92, 95, 97, 98, 100, 101, 104 to 107, 116, 122, 126, 128, 130 to 134, 143, 145, 148, 151, 153, 154, 157, and 160 to 163. For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0056] In one embodiment, the antisense oligonucleotide of the present invention is selected from those in which the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells to the ATN-1 gene expression level when administered with the positive control antisense oligonucleotide OMe-6 or NRH-71 is 0.5 or less in any of the examples, when measured according to the method described in the examples of the present specification. Examples of such antisense oligonucleotides include antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to nucleic acids containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1598 to 1626, 1870 to 1890, 2097 to 2116, 2711 to 2736, 2841 to 2860, and 4170 to 4198 of the base sequence of SEQ ID NO: 471. Further examples include antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1598 to 1617, 1604 to 1623, 1607 to 1626, 1870 to 1889, 1871 to 1890, 2097 to 2116, 2711 to 2730, 2714 to 2733, 2717 to 2736, 2841 to 2860, 4170 to 4189, 4173 to 4192, and 4179 to 4198 of the base sequence of SEQ ID NO:471.

[0057] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163, in which one or several bases have been added, deleted, or substituted; or (iii) a base sequence having 90% or more sequence identity to a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163; For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0058] In one embodiment, the antisense oligonucleotide of the present invention is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 400 to 425, 1581 to 1624, 1878 to 1898, 2094 to 2113, 2629 to 2656, 2700 to 2741, 2839 to 2863, 2962 to 2981, 3302 to 3325, 3631 to 3658, 3687 to 3714, 3745 to 3764, 3980 to 4007, 4177 to 4199, and 4204 to 4223 of the base sequence of SEQ ID NO: 471.

[0059] In one embodiment, the antisense oligonucleotide of the present invention is selected from the group consisting of positions 400 to 419, 403 to 422, 406 to 425, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1590 to 1609, 1591 to 1610, 1592 to 1611, 1593 to 1612, 1594 to 1613, 1595 to 1614, 1596 to 1615, 1597 to 1616, 1598 to 1617, 1599 to 1620, 1591 to 1621, 1592 to 1622, 1593 to 1623, 1594 to 1624, 1595 to 1625, 1596 to 1626, 1597 to 1628, 1598 to 1629, 1599 to 1630, 1599 to 1631, 1598 to 1632, 1599 to 1640, 1590 to 1641, 1591 to 1642, 1592 to 1643, 1593 to 1644, 1594 to 1645, 1595 to 1646, 1596 to 1647, 1597 to 1648, 1598 to 1649, 159 615th, 1597th to 1616th, 1599th to 1618th, 1600th to 1619th, 1602nd to 1621st, 1603rd to 1622nd, 1605th to 1624th, 1878th to 1897th, 1879th to 1898th, 2094th to 2113th , 2629th to 2648th, 2637th to 2656th, 2700th to 2719th, 2701st to 2720th, 2703rd to 2722nd, 2704th to 2723rd, 2706th to 2725th, 2707th to 2726th, 2709th to 2728th, 2710 ~2729th, 2712~2731, 2713~2732, 2715~2734, 2716~2735, 2718~2737, 2719~2738, 2721~2740, 2722~2741, 2839~28 58th, 2840th to 2859th, 2842nd to 2861st, 2843rd to 2862nd, 2844th to 2863rd, 2962nd to 2981st, 3302nd to 3321st, 3306th to 3325th, 3631st to 3650th, 3632nd to 3651st, 3 It is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 633 to 3652, 3634 to 3653, 3636 to 3655, 3637 to 3656, 3638 to 3657, 3639 to 3658, 3687 to 3706, 3695 to 3714, 3745 to 3764, 3980 to 3999, 3988 to 4007, 4177 to 4196, 4178 to 4197, 4180 to 4199, and 4204 to 4223.

[0060] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355. For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0061] In one embodiment, the antisense oligonucleotide of the present invention is selected from those in which, when measured according to the method described in the Examples of the present specification, the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells to the ATN-1 gene expression level when administered with the positive control antisense oligonucleotides OMe-6 or NRH-71 is 1.0 or less in any of the Examples. Examples of such antisense oligonucleotides include antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 400 to 425, 1581 to 1624, 1878 to 1898, 2637 to 2656, 2700 to 2741, 2839 to 2863, 2962 to 2981, 3302 to 3325, 3631 to 3658, 3687 to 3706, 3745 to 3764, 4177 to 4199, and 4204 to 4223 of the base sequence of SEQ ID NO:471.In addition, positions 400 to 419, 403 to 422, 406 to 425, 1581 to 1600, 1582 to 1601, 1583 to 1602, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1591 to 1610, 1592 to 1611, 1593 to 1612, 1594 to 1613, 1596 to 1615, 1597 to 1616, 1600 to 1601, 1598 to 1602, 1599 to 1613, 1590 to 1603, 1591 to 1604, 1592 to 1605, 1593 to 1606, 1594 to 1617, 1595 to 1607, 1596 to 1618, 1597 to 1619, 1598 to 1620, 1599 to 1621, 1599 to 1622, 1599 to 1623, 1599 to 1624, 1590 to 1625, 1591 to 1626, 1591 to 1627, 1592 to 1628, 1593 to 1629, 1594 to 1630, 1595 to 1631, 1596 to 1632, 1597 to 1633, 1598 to 1634, 1599 to 16 ~1619th, 1602~1621, 1603~1622, 1605~1624, 1878~1897, 1879~1898, 2637~2656, 2700~2719, 2701~2720 , 2703rd ~ 2722nd, 2704th ~ 2723rd, 2706th ~ 2725th, 2707th ~ 2726th, 2709th ~ 2728th, 2710th ~ 2729th, 2712th ~ 2731st, 2713th ~ 2732nd, 2715th ~ 2734th, 2716~2735, 2718~2737, 2719~2738, 2721~2740, 2722~2741, 2839~2858, 2840~2859, 2842~2861, 2 843rd to 2862nd, 2844th to 2863rd, 2962nd to 2981st, 3302nd to 3321st, 3306th to 3325th, 3631st to 3650th, 3632nd to 3651st, 3633rd to 3652nd, 3634th to 36th and antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 53, 3636 to 3655, 3637 to 3656, 3638 to 3657, 3639 to 3658, 3687 to 3706, 3745 to 3764, 4177 to 4196, 4178 to 4197, 4180 to 4199, and 4204 to 4223.

[0062] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 171, 173 to 177, 179 to 184, 187 to 214, 216, 219 to 222, 233 to 234, and 350 to 355. For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0063] In one embodiment, the antisense oligonucleotide of the present invention is selected from those in which the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells to the ATN-1 gene expression level when administered with the positive control antisense oligonucleotide OMe-6 or NRH-71 is 0.75 or less in any of the examples, when measured according to the method described in the examples of the present specification. Examples of such antisense oligonucleotides include antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to nucleic acids containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1581 to 1624, positions 2703 to 2740, positions 3633 to 3655, and positions 4177 to 4199 of the base sequence of SEQ ID NO: 471. In addition, the amino acid sequences of the base sequence of SEQ ID NO:471 at positions 1581 to 1600, 1582 to 1601, 1584 to 1603, 1585 to 1604, 1587 to 1606, 1588 to 1607, 1594 to 1613, 1596 to 1615, 1597 to 1616, 1602 to 1621, 1603 to 1622, 1605 to 1624, 2703 to 2722, 2707 to 2726, 2709 to 2728, 2710 to 2729, 2712 to 2731, 2713 to 2732, 2714 to 2736, 2715 to 2738, 2716 to 2739, 2720 to 2740, 2721 to 2741, 2722 to 2742, 2723 to 2743, 2724 to 2744, 2725 to 2746, 2726 to 2747, 2728 to 2749, 2730 to 2749, 2731 to 2748, 2732 to 2749, 2749 to 2750, 2751 to 2752, 2753 to 2754, 2755 to 2756, 2757 to 2758, 2759 to 2760, 2761 to 2762, 2763 to 2764, 2765 to 27 and antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 3 to 2732, 2715 to 2734, 2716 to 2735, 2718 to 2737, 2719 to 2738, 2721 to 2740, 3633 to 3652, 3634 to 3653, 3636 to 3655, 4177 to 4196, 4178 to 4197, and 4180 to 4199.

[0064] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 167 to 171, 175 to 177, 180 to 182, 190, 193 to 202, 219 to 221, 233, and 351 to 353. For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0065] In one embodiment, the antisense oligonucleotide of the present invention is selected from those in which the ratio (average value) of the ATN-1 gene expression level when administered to A204 cells to the ATN-1 gene expression level when administered with the positive control antisense oligonucleotide OMe-6 or NRH-71 is 0.5 or less in any of the examples, when measured according to the method described in the examples of the present specification. Examples of such antisense oligonucleotides include antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1587 to 1616, positions 2712 to 2735, and positions 4180 to 4199 of the base sequence of SEQ ID NO: 471. Further examples include antisense oligonucleotides consisting of 15 to 22 nucleotides that are complementary to a nucleic acid containing at least 15 consecutive bases in a target region selected from the group consisting of positions 1587 to 1606, 1597 to 1616, 2712 to 2731, 2716 to 2735, and 4180 to 4199 of the base sequence of SEQ ID NO:471.

[0066] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199, and 221; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199, and 221, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199, and 221 For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0067] In one embodiment, the present invention relates to a nucleic acid sequence encoding a nucleic acid fragment having a nucleic acid sequence of SEQ ID NO: 471 at positions 468 to 487, 474 to 493, 583 to 602, 586 to 605, 619 to 638, 770 to 789, 774 to 793, 775 to 794, 778 to 797, 804 to 823, 851 to 870, 1160 to 1179, 1162 to 1181, 1170 to 1189, 1173 to 1192, 1205 to 1224, 1210 to 1229, 1216 to 1235, 1217 to 1236, 1219 to 1238, 13 The present invention relates to an antisense oligonucleotide consisting of 15 to 22 nucleotides, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 85 to 1404, 1441 to 1460, 1818 to 1837, 1902 to 1921, 1905 to 1924, 1908 to 1927, 1914 to 1933, 1931 to 1950, 2117 to 2136, 2749 to 2768, 3100 to 3119, and 4125 to 4144, or a pharma- ceutically acceptable salt or hydrate thereof.

[0068] Examples of antisense oligonucleotides complementary to a nucleic acid containing at least 15 consecutive bases in the target sequence include: (i) a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146, and 159; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146, and 159, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146, and 159. For example, there is an antisense oligonucleotide comprising or consisting of the base sequence of (i).

[0069] In one embodiment, the antisense oligonucleotide of the present invention inhibits the function of the target region. As used herein, "inhibiting the function of the target region" includes one or more of the following: cleavage by RNase H of the genomic RNA containing the target region that has bound to the target region and formed a double strand with the antisense oligonucleotide; inhibition of replication of the genomic RNA containing the target region; inhibition of translation of the target region when it is translated; and inhibition of transcription of the genomic RNA containing the target region. As used herein, "subgenomic RNA" refers to a subgenomic RNA synthesized by RNA-dependent RNA polymerase using a portion of the (-) strand RNA as a template. It refers to RNA that is shorter than genomic RNA and serves as mRNA for viral protein synthesis (translation).

[0070] The antisense oligonucleotides of the present invention can be easily synthesized using various automated synthesizers (e.g., AKTA oligopilot plus 10 / 100 (GE Healthcare)), or can be produced by outsourcing to a third party (e.g., Promega or Takara).

[0071] In one embodiment, the present invention relates to a pharmaceutical composition comprising an antisense oligonucleotide or its pharma- ceutically acceptable salt or hydrate thereof.When administering the antisense nucleotide of the present invention to a subject, the pharmaceutical composition of the present invention may comprise a carrier that promotes the delivery of the antisense nucleotide.Such a carrier is not particularly limited as long as it is pharma- cetically acceptable, and examples thereof include a cationic carrier such as a cationic liposome or a cationic polymer, or a carrier that utilizes a virus envelope. Examples of cationic liposomes include liposomes formed with 2-O-(2-diethylaminoethyl)carbamoyl-1,3-O-dioleoylglycerol and phospholipids as essential components (hereinafter referred to as "Liposome A"), Oligofectamine (registered trademark) (Invitrogen), Lipofectin (registered trademark) (Invitrogen), Lipofectamine (registered trademark) (Invitrogen), Lipofectamine 2000 (registered trademark) (Invitrogen), DMRIE-C (registered trademark) (Invitrogen), GeneSilencer (registered trademark) (Gene Therapy Systems), TransMessenger (registered trademark) (QIAGEN), TransIT TKO (registered trademark) (Mirus), and Nucleofector II (Lonza). Examples of cationic polymers include JetSI (registered trademark) (Qbiogene) and Jet-PEI (registered trademark) (polyethyleneimine, Qbiogene). Examples of carriers using viral envelopes include GenomeOne (registered trademark) (HVJ-E liposome, Ishihara Sangyo Kaisha). Alternatively, the pharmaceutical device described in Japanese Patent No. 2924179, and the cationic carriers described in Republished Patent Publication No. 2006 / 129594 and Republished Patent Publication No. 2008 / 096690 can also be used.

[0072] In one embodiment, the antisense oligonucleotide of the present invention may be conjugated with lipids or the like in a pharmaceutical composition to facilitate delivery of the antisense oligonucleotide.For example, it may be conjugated with cholesterol as described in Bijsterbosch, MK et al. (2000) Nucleic Acid Res., 28, 2717-2725.

[0073] The pharmaceutical composition of the present invention may contain pharma- ceutical acceptable additives in addition to the antisense oligonucleotide or its pharma- ceutical acceptable salt or hydrate thereof and, optionally, the above-mentioned carrier. Examples of such additives include emulsifiers (e.g., fatty acids having 6 to 22 carbon atoms or their pharma- ceutical acceptable salts, albumin, and dextran), stabilizers (e.g., cholesterol, phosphatidic acid, mannitol, and sorbitol), isotonicity agents (e.g., sodium chloride, glucose, maltose, lactose, sucrose, and trehalose), and pH adjusters (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, and triethanolamine). One or more of these may be used. The content of the additive in the composition of the present invention is suitably 90% by weight or less, preferably 70% by weight or less, and more preferably 50% by weight or less.

[0074] The method of preparation of the pharmaceutical composition of the present invention is not limited, but for example, the antisense oligonucleotide of the present invention can be added to the dispersion of the carrier and appropriately stirred to prepare the pharmaceutical composition. In addition, additives can be added at an appropriate step before or after the addition of the antisense oligonucleotide of the present invention. The aqueous solvent that can be used when adding the antisense oligonucleotide of the present invention is not particularly limited as long as it is medicamentously acceptable, and examples thereof include water for injection, distilled water for injection, electrolyte solution such as physiological saline, sugar solution such as glucose solution, maltose solution, etc. In addition, conditions such as pH and temperature in such cases can be appropriately selected by those skilled in the art.

[0075] The pharmaceutical composition of the present invention can be, for example, a liquid or a freeze-dried preparation thereof. The freeze-dried preparation can be prepared by freeze-drying the composition of the present invention in the form of a liquid by a conventional method. For example, after the composition of the present invention in the form of a liquid is appropriately sterilized, a predetermined amount is dispensed into a vial, pre-freezing is performed for about 2 hours under conditions within the range of about -40°C to -20°C, primary drying is performed under reduced pressure within the range of about 0°C to 10°C, and then secondary drying is performed under reduced pressure within the range of about 15°C to 25°C to freeze-dry. Then, the inside of the vial is generally replaced with nitrogen gas, and the vial is sealed to obtain a freeze-dried preparation of the composition of the present invention.

[0076] The lyophilized preparation of the pharmaceutical composition of the present invention can generally be reconstituted and used by adding any suitable solution (reconstitution liquid). Examples of such reconstitution liquid include water for injection, physiological saline, and other general infusion liquids. The amount of the reconstitution liquid varies depending on the application, etc., and is not particularly limited, but is suitably 0.5 to 2 times the amount of the liquid before lyophilization or 500 mL or less.

[0077] The dosage of the pharmaceutical composition of the present invention is preferably adjusted taking into consideration the type of antisense oligonucleotide of the present invention contained therein, the dosage form, the condition of the patient such as age and body weight, the administration route, and the nature and degree of the disease. The amount of the antisense oligonucleotide of the present invention can be 0.01 mg to 20 mg per kg of body weight, preferably 0.03 mg to 10 mg per kg of body weight, more preferably 0.05 mg to 4 mg per kg of body weight, and more preferably 0.1 mg to 2 mg per kg of body weight per administration for adults. The administration frequency may be once every 1 to 3 days, once a week, or once every 2 to 3 weeks. This value may vary depending on the type of disease to be targeted, the administration form, and the target molecule. Therefore, in some cases, a dosage or administration frequency less than this may be sufficient, and conversely, a dosage or administration frequency greater than this may be required.

[0078] The administration form of the pharmaceutical composition of the present invention is not particularly limited as long as it is a pharma- ceutical acceptable administration form, and can be selected according to the treatment method, and examples thereof include intravenous administration, intraarterial administration, intramuscular administration, subcutaneous administration, oral administration, intratissue administration, transdermal administration, pulmonary administration, nasal administration, administration to the central nervous system, etc. Examples of administration to the central nervous system include intrathecal administration, intracranial administration, for example, intraventricular administration or lateral ventricular administration, intraparenchymal administration, and subpial administration. In addition, the dosage form that the composition of the present invention can take is not particularly limited, and examples thereof include various injections, oral agents, infusions, inhalants, ointments, lotions, poultices, etc.

[0079] Subjects to which the antisense oligonucleotide or pharmaceutical composition of the present invention is administered include, for example, mammals, such as primates such as humans, laboratory animals such as rats, mice, and rats, and livestock animals such as pigs, cows, horses, and sheep, and preferably humans.

[0080] In one embodiment, the present invention relates to a method for treating and / or preventing dentatorubral-pallidoluysian atrophy (DRPLA), comprising administering to a subject the antisense oligonucleotide of the present invention, or a pharma- ceutical composition thereof, or a pharmaceutical composition thereof. The pharmaceutical composition in this embodiment, as well as the dosage and administration route of the pharmaceutical composition, are as described herein.

[0081] As used herein, treatment of dentatorubral-pallidoluysian atrophy (DRPLA) includes one or more of alleviating, ameliorating, and remission of dentatorubral-pallidoluysian atrophy or its symptoms (e.g., one or more of ataxia, myoclonus, epilepsy, and progressive intellectual deterioration in children, and ataxia, choreoathetosis, dementia, or personality changes in adults). As used herein, prevention of DRPLA includes reducing the risk of developing DRPLA or its symptoms. EXAMPLES

[0082] The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited to the scope shown in the examples.

[0083] A "gapmer" is defined as an oligomeric compound, generally an oligonucleotide, that has a central region of 2'-deoxyoligonucleotide flanked by two flanking segments of non-deoxyoligonucleotide. The central region is called the "gap" and the flanking segments are called the "wings." The gapmer used in this example has a 10 nucleotide gap flanked by two flanking wings of 5 nucleotides. This is called a 5-10-5 gapmer.

[0084] Example 1: Synthesis of gapmers (oligonucleotides) The gapmers (oligonucleotides) used in this example can generally be produced according to the methods described in W. Brad Wan et al., Nucleic Acid Research, Vol. 42, No. 22 13456 (2014), etc.

[0085] Among the gapmers used in this example, some of the specific oligonucleotides having a 2'-methoxy (2'-OMe) group represented by formula (a) in the wing nucleoside were synthesized with reference to the method described in W. Brad Wan et al., Nucleic Acid Research, Vol. 42, No. 22 13456 (2014) as described above. The remaining ones were obtained by outsourcing the synthesis to Gene Design Co., Ltd.

[0086] [ka] (In the formula, Base is cytosine (C), uracil (U), adenine (A), or guanine (G), and Me is methyl.) Among the gapmers used in this example, a specific oligonucleotide having a 2'-methoxyethyl (2'-O-MOE) group represented by formula (b) on the wing nucleoside was synthesized with reference to the method described in W. Brad Wan et al., Nucleic Acid Research, Vol. 42, No. 22 13456 (2014) as described above.

[0087] [ka] (In the formula, Base is 5-methylcytosine (C), thymine (T), adenine (A), or guanine (G), and Me is methyl.)

[0088] The 20-mer test gapmers (oligonucleotides) having a 2'-OMe group represented by formula (a) or a 2'-O-MOE group represented by formula (b) on the wing nucleoside were synthesized on a 1 μmol scale using an automatic nucleic acid synthesizer NTS M-8-MX DNA / RNA (Nihon Techno Service Co., Ltd.). Chain length was extended using a standard phosphoramidite protocol (solid support: Glen UnySupport, sulfurization was performed using DDTT ([(N,N-Dimethylaminomethylidene)amino]-3H-1,2,4-dithiazoline-3-thione) or the like, and oxidation was performed using 0.02M iodine / tetrahydrofuran:pyridine:water = 7:1:2 or the like), and an oligonucleotide in which the hydroxyl group at the terminal 5' position was protected with a dimethoxytrityl (DMTr) group and the 3' position was supported on the solid phase was obtained. The DMTr group was then removed by treatment with Deblocking Solution-1 (available from Fuji Film Wako Co., Ltd.), and the target product was then cleaved from the solid support by treatment with ammonia. The solvent was removed, and the resulting crude product was purified by reversed-phase HPLC to obtain the target product.

[0089] Example 2: Design of gapmers (oligonucleotides) for test subjects The subject gapmers (oligonucleotides) were designed as antisense oligonucleotides (ASOs) targeting human atrophin-1 (ATN1) (Gen Bank: NM_001007026, SEQ ID NO: 471). The sequences of the oligonucleotides, expressed in DNA bases, are shown in Tables 1, 2, 3, and 4.

[0090] In Tables 1 and 2, all of the oligonucleotides are 5-10-5 gapmers, and all of the internucleoside linkages are phosphorothioate (P=S). For the gapmers with 2'-OMe groups in Table 1, the T (thymine) in the wing portion is actually U (uracil). For the gapmers with 2'-O-MOE groups in Table 2, the C (cytosine) in the gap portion and the wing portion is actually methyl C, and the T in the wing portion is actually T.

[0091] [Table 1] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] In Table 3, all oligonucleotides are 5-10-5 gapmers with 2'-O-MOE groups, the internucleoside linkages in the 5' and 3' wing portions are phosphorothioate (P=S) or phosphodiester (P=O), and all internucleoside linkages in the gap portion are phosphorothioate (P=S). In Table 3, phosphodiester (P=O) linkages are indicated by ^. Also, the C in the gap portion and the wing portion are actually methyl C, and the T in the wing portion are actually T. [Table 3] In Table 4, all oligonucleotides are 5-10-5 gapmers with 2'-O-MOE groups, the internucleoside bonds in the 5' and 3' wing portions are phosphorothioate (P=S) or phosphodiester (P=O), and all internucleoside bonds in the gap portion are phosphorothioate (P=S). In Table 4, phosphodiester (P=O) bonds are indicated by ^. Additionally, the C in the gap portion and the wing portion is actually a methyl C, the T in the wing portion is actually a T, and the underlined base in the 3' wing portion is a base that differs from SEQ ID NO: 196. [Table 4]

[0092] [Test Example 1] Assay of ATN-1 gene knockdown activity (inhibitory activity) of gapmers using A204 human rhabdomyosarcoma cell line A204 cells (obtained from ATCC) 3.0 × 10 5The cells were transfected with the test gapmer or positive control gapmer in Table 1 or Table 2 at a concentration of 1 μM or 2 μM using SF Cell Line 4D-Nucleofector(TM) X KitS according to the protocol attached to the kit. The program used was DS-130. After transfection, the cells were cultured overnight in McCoy's 5A Medium (SIGMA) containing 10% fetal bovine serum (FBS) (NICHIREI) and 1 mM L-glutamine (Gibco) under 37°C and 5% CO2 conditions. The positive control gapmers used were OMe-6 (5'-AGAGACCTGGTCCAAGATTC-3', SEQ ID NO: 472) with 2'-OMe groups at the wing nucleosides or NRH-71 (5'-AGAGACCTGGTCCAAGATTC-3', SEQ ID NO: 472) with 2'-O-MOE groups at the wing nucleosides, whose activity was confirmed by preliminary tests (data not shown). Both oligonucleotides were 5-10-5 gapmers, and all internucleoside bonds were phosphorothioate (P=S). For OMe-6, the T (thymine) in the wing portion was actually U (uracil). For NRH-71, the C (cytosine) in the gap portion and wing portion was actually methyl C, and the T in the wing portion was actually T. These positive control gapmers were also synthesized in the same manner as the gapmers to be tested. The next day, the cells were washed with PBS (Nacalai Tesque), then RA1 (Takara Bio) containing 1% 2-mercaptoethanol (Nacalai Tesque) was added to dissolve the cells, and the cells were collected on a NucleoSpin® Filter (Takara Bio). After removing the insoluble fraction by centrifugation, total RNA was extracted according to the protocol attached to the NucleoSpin® RNA (Takara Bio). The concentration of the extracted total RNA was measured using a NanoDrop (Thermo Fisher).Reverse transcription (RT) reaction was carried out on 200 ng of extracted total RNA using the High Capacity cDNA Reverse Transcription Kit (applied biosystems) and the random primers included with the kit. Specifically, the reaction solution was prepared according to the protocol attached to the kit. The thermal cycler used was a TaKaRa PCR Thermal Cycler Dice Touch (Takara Bio). The RT reaction program used was as follows.

[0093] 25℃, 10 min: primer annealing 37℃, 120 minutes: Reverse transcription reaction 85℃, 5 minutes: reverse transcriptase inactivation Then, qPCR was performed using Fast SYBR Green Master Mix (Thermo Fisher Scientific) with the RT reaction mixture as a template to measure the RNA expression level of ATN1 endogenously expressed in A204 cells. 7) was used as a template. Specifically, the reaction solution was prepared according to the protocol attached to the above kit. For qPCR, the QuantStudio6Flex Real-Time PCR System (applied biosystems) was used. The qPCR program used was as follows.

[0094] 50℃, 2 min; 95℃, 10 min: Polymerase activation, cDNA denaturation [95°C, 15 seconds; 60°C, 1 minute] x 40 cycles: PCR amplification 95℃, 15 seconds; 60℃, 1 minute → 95℃, 15 seconds (Melting Curve 0.05℃ / s): Melting curve analysis The primers used for detecting ATN1 RNA are shown in Table 4. The expression level of ATN1 RNA was normalized by the expression level of the housekeeping gene β-actin RNA. The primers used for RNA detection are shown in Table 4. The inhibition rate of ATN1 RNA expression in cells that were not added with gapmer and were only transfected with 4D-Nucleofector™ was calculated from the ratio of ATN1 RNA expression when the gapmer of the test substance was transfected, and the gapmer inhibitory activity of the test substance was analyzed. The results are shown in Tables 5 to 9.

[0095] [Table 5-1] [Table 5-2] [Table 6-1] [Table 6-2] [Table 7] [Table 8-1] [Table 8-2] [Table 9] [Table 10-1] [Table 10-2] [Table 11-1] [Table 11-2] [Table 11-3]

Claims

1. Positions 1 to 84, 142 to 168, 197 to 224, 286 to 317, 324 to 370, 391 to 434, 519 to 540, 623 to 643, 690 to 780, 824 to 855, 860 to 897, 948 to 987, 1044 to 1072, 1125 to 1174, and 1181 to 1213 of the base sequence of SEQ ID NO:471 , 1228th to 1255th, 1265th to 1327th, 1334th to 1356th, 1416th to 1440th, 1447th to 1631st, 1638th to 1667th, 1675th to 1705th 1748th to 1823rd, 1838th to 1861st, 1870th to 1913th, 1920th to 1941st, 2000th to 2040th, 2047th to 2075th, 2086th to 212th 0th place, 2129th - 2187th, 2194th - 2415th, 2451st - 2497th, 2592nd - 2759th, 2766th - 2870th, 2928th - 2948th, 2955th - 2 989th, 3021st to 3086th, 3133rd to 3209th, 3217th to 3284th, 3295th to 3350th, 3384th to 3436th, 3562nd to 3771st, 3858th to An antisense oligonucleotide consisting of 15 to 22 nucleotides, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a region selected from the group consisting of positions 3905, 3931 to 4039, 4067 to 4134, 4170 to 4232, 4241 to 4283, and 4286 to 4355, or a pharma- ceutically acceptable salt or hydrate thereof.

2. 1 to 69, 331 to 363, 398 to 427, 697 to 773, 867 to 890, 955 to 980, 1132 to 1167, 1272 to 1320, 1454 to 1624, 1682 to 1705, 1748 to 1816, 1877 to 1906, 2007 to 2033, 2093 to 2113, 2136 to 2180, 2201 to 2408, 2458 to 2490, 2599 to 2752, 2773 to 2863, 2962 to 2982, The antisense oligonucleotide according to claim 1, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 3028 to 3079, 3140 to 3202, 3224 to 3277, 3302 to 3343, 3391 to 3429, 3569 to 3764, 3865 to 3898, 3938 to 4032, 4074 to 4127, 4177 to 4225, 4248 to 4276, and 4293 to 4355.

3. positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 432, 723 to 742, 747 to 778, 965 to 984, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1228 to 1254, 1270 to 1308, 1484 to 1564, 157 8th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1913th, 2015th to 2034th, 2086th to 2118th, 2129th to 2148th, 2151st to 2184th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373th 2387th - 2406th, 2598th - 2757th, 2775th - 2809th, 2826th - 2866th, 2959th - 2982nd, 3032nd - 3051st, 3052nd - 3 071st, 3136th to 3155th, 3168th to 3187th, 3188th to 3207th, 3232nd to 3270th, 3298th to 3344th, 3408th to 3427th, 3563 2. The antisense oligonucleotide according to claim 1, or a pharma- ceutically acceptable salt or hydrate thereof, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 3582 to 3582, 3590 to 3728, 3739 to 3769, 3877 to 3896, 3949 to 4030, and 4170 to 4225.

4. 14-33, 34-53, 54-73, 148-167, 397-416, 398-417, 399-418, 400-419, 401-420, 402-421, 403-422, 404-423, 405-424, 406-425, 407-426, 408-427, 413-432, 723-742, 747-766, 756-775, 759-778, 965-984, 1127-1146, 1148-116 7th place, 1151st to 1170th, 1154th to 1173rd, 1182nd to 1201st, 1185th to 1204th, 1188th to 1207th , 1191st to 1210th, 1194th to 1213th, 1228th to 1247th, 1231st to 1250th, 1235th to 1254th, 1 270th to 1289th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 1510th, 149 3rd to 1512th, 1506th to 1525th, 1517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1579th to 1598th, 1580th to 1599th, 1581st to 1600th, 1582nd to 1601st, 1583rd to 16th 02nd place, 1584th to 1603rd, 1585th to 1604th, 1586th to 1605th, 1587th to 1606th, 1588th to 1607th 1589th to 1608th, 1590th to 1609th, 1591st to 1610th, 1592nd to 1611th, 1593rd to 1612th, 1594th to 1613th, 1595th to 1614th, 1596th to 1615th, 1597th to 1616th, 1598th to 1617th, 159 9th to 1618th, 1600th to 1619th, 1601st to 1620th, 1602nd to 1621st, 1603rd to 1622nd, 1604th ~1623rd place, 1605th place - 1624th place, 1607th place - 1626th place, 1610th place - 1629th place, 1686th place - 1705th place, 1748th place - 1 767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1889th, 1871st to 1890th, 1874th to 189th 3rd place, 1877th to 1896th, 1878th to 1897th, 1879th to 1898th, 1880th to 1899th, 1881st to 1900th,1882-1901, 1883-1902, 1884-1903, 1885-1904, 1886-1905, 1887-1906, 1889-1908, 1894-1913, 2015-2034, 2086-2105, 2093 2094-2113, 2097-2116, 2099-2118, 2129-2148, 2151-2170, 2165-2184, 2206-2225, 2239-2258, 2253-2272, 2287-230 6, 2301-2320, 2317-2336, 2337-2356, 2354-2373, 2387-2406, 2598-2617, 2613-2632, 2614-2633, 2615-2634, 2616-2635, 2 617 to 2636, 2618 to 2637, 2619 to 2638, 2620 to 2639, 2621 to 2640, 2622 to 2641, 2623 to 2642, 2624 to 2643, 2625 to 2644, 2626 to 2645, 2627 to 2646, 2628-2647, 2629-2648, 2630-2649, 2631-2650, 2632-2651, 2633-2652, 2634-2653, 2635-2654, 2636-2655, 2637-2656 2638-2657, 2639-2658, 2640-2659, 2641-2660, 2642-2661, 2643-2662, 2644-2663, 2645-2664, 2646-2665, 2647-2666, 264 8 to 2667, 2649 to 2668, 2663 to 2682, 2672 to 2691, 2673 to 2692, 2674 to 2693, 2675 to 2694, 2676 to 2695, 2677 to 2696, 2678 to 2697, 2679 to 2 698, 2680-2699, 2681-2700, 2682-2701, 2683-2702, 2684-2703, 2685-2704, 2686-2705, 2687-2706, 2688-2707, 2689-2708,2690-2709, 2691-2710, 2692-2711, 2693-2712, 2694-2713, 2695-2714, 2696-2715, 2697-2716, 2698-2717, 2699-2718, 2700 2701-2720, 2702-2721, 2703-2722, 2704-2723, 2705-2724, 2706-2725, 2707-2726, 2708-2727, 2709-2728, 2710-272 9, 2711-2730, 2712-2731, 2713-2732, 2714-2733, 2715-2734, 2716-2735, 2717-2736, 2718-2737, 2719-2738, 2720-2739, 2 721 to 2740, 2722 to 2741, 2723 to 2742, 2724 to 2743, 2725 to 2744, 2726 to 2745, 2727 to 2746, 2728 to 2747, 2729 to 2748, 2730 to 2749, 2731 to 2750, 2732-2751, 2733-2752, 2738-2757, 2775-2794, 2790-2809, 2826-2845, 2827-2846, 2828-2847, 2829-2848, 2830-2849 2831-2850, 2832-2851, 2833-2852, 2834-2853, 2835-2854, 2836-2855, 2837-2856, 2838-2857, 2839-2858, 2840-2859, 2841-2843 1st to 2860th, 2842nd to 2861st, 2843rd to 2862nd, 2844th to 2863rd, 2847th to 2866th, 2959th to 2978th, 2962nd to 2981st, 2963rd to 2982nd, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3141st 155, 3168-3187, 3188-3207, 3232-3251, 3251-3270, 3298-3317, 3302-3321, 3303-3322, 3304-3323, 3305-3324, 3306-3325,3307-3326, 3308-3327, 3309-3328, 3310-3329, 3311-3330, 3312-3331, 3313-3332, 3314-3333, 3315-3334, 3316-3335, 3317 3324-3325, 3326-3328, 3329-3339, 3330-3331, 3331-3332, 3332-3333, 3333-3334, 3334-3335, 3336-3337, 3338-3339, 3340-3341, 3342-3343, 3344-3345, 3408-3427, 3563-358 2, 3590-3609, 3608-3627, 3617-3636, 3618-3637, 3619-3638, 3620-3639, 3621-3640, 3622-3641, 3623-3642, 3624-3643, 3 625 to 3644, 3626 to 3645, 3627 to 3646, 3628 to 3647, 3629 to 3648, 3630 to 3649, 3631 to 3650, 3632 to 3651, 3633 to 3652, 3634 to 3653, 3635 to 3654, 3636-3655, 3637-3656, 3638-3657, 3639-3658, 3640-3659, 3641-3660, 3642-3661, 3643-3662, 3644-3663, 3645-3664 3646-3665, 3647-3666, 3648-3667, 3649-3668, 3650-3669, 3651-3670, 3652-3671, 3653-3672, 3654-3673, 3671-3690, 367 2nd to 3691st, 3673rd to 3692nd, 3674th to 3693rd, 3675th to 3694th, 3676th to 3695th, 3677th to 3696th, 3678th to 3697th, 3679th to 3698th, 3680th to 3699th, 3681st to 3700th, 3682nd to 3 701, 3683-3702, 3684-3703, 3685-3704, 3686-3705, 3687-3706, 3688-3707, 3689-3708, 3690-3709, 3691-3710, 3692-3711,3693rd to 3712th, 3694th to 3713th, 3695th to 3714th, 3696th to 3715th, 3697th to 3716th, 3698th to 3717th, 3699th to 3718th, 3700th to 3719th, 3701st to 3720th, 3702nd to 3721st, 3703rd 3704-3723, 3705-3724, 3706-3725, 3707-3726, 3708-3727, 3709-3728, 3739-3758, 3740-3759, 3741-3760, 3742-3764 1, 3743rd to 3762nd, 3744th to 3763rd, 3745th to 3764th, 3750th to 3769th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3965th to 3984th, 3966th to 3985th, 3967th to 3986th, 3 968th to 3987th, 3969th to 3988th, 3970th to 3989th, 3971st to 3990th, 3972nd to 3991st, 3973rd to 3992nd, 3974th to 3993rd, 3975th to 3994th, 3976th to 3995th, 3977th to 3996th, 3978th ​​to 3997, 3979 to 3998, 3980 to 3999, 3981 to 4000, 3982 to 4001, 3983 to 4002, 3984 to 4003, 3985 to 4004, 3986 to 4005, 3987 to 4006, 3988 to 4007 3989-4008, 3990-4009, 3991-4010, 3992-4011, 3993-4012, 3994-4013, 3995-4014, 3996-4015, 3997-4016, 3998-4017, 399 9th to 4018th, 4011th to 4030th, 4170th to 4189th, 4173rd to 4192nd, 4176th to 4195th, 4177th to 4196th, 4178th to 4197th, 4179th to 4198th, 4180th to 4199th, 4181st to 4200th, 4182nd to 4 201, 4183-4202, 4184-4203, 4185-4204, 4186-4205, 4187-4206, 4188-4207, 4189-4208, 4190-4209, 4191-4210, 4192-4211,The antisense oligonucleotide according to claim 3, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 4193 to 4212, 4194 to 4213, 4195 to 4214, 4196 to 4215, 4197 to 4216, 4198 to 4217, 4199 to 4218, 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224, and 4206 to 4225.

5. positions 14 to 33, 34 to 53, 398 to 427, 723 to 742, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1564, 1578 to 1624, 1686 to 1705, 1748 to 1767, 1 768th to 1787th, 1794th to 1813th, 1877th to 1906th, 2093rd to 2113th, 2151st to 2170th, 2206th to 2 225th, 2239th to 2272nd, 2287th to 2336th, 2337th to 2373rd, 2387th to 2406th, 2613th to 2752nd, 2 The antisense oligonucleotide according to claim 2 or 3, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 775 to 2809, positions 2826 to 2863, positions 2962 to 2982, positions 3032 to 3051, positions 3052 to 3071, positions 3168 to 3187, positions 3232 to 3270, positions 3302 to 3343, positions 3408 to 3427, positions 3590 to 3728, positions 3739 to 3764, positions 3877 to 3896, positions 3949 to 4030, and positions 4177 to 4225, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

6. positions 14 to 33, 34 to 53, 398 to 417, 399 to 418, 400 to 419, 401 to 420, 402 to 421, 403 to 422, 404 to 423, 405 to 424, 406 to 425, 407 to 426, 408 to 427, 723 to 742, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1506 to 1525, 1517 to 1528, 1536th, 1531st to 1550th, 1545th to 1564th, 1578th to 1597th, 1579th to 1598th, 1580th to 15th 99th place, 1581st to 1600th, 1582nd to 1601st, 1583rd to 1602nd, 1584th to 1603rd, 1585th to 1604th , 1586th to 1605th, 1587th to 1606th, 1588th to 1607th, 1589th to 1608th, 1590th to 1609th, 1 591st to 1610th, 1592nd to 1611th, 1593rd to 1612th, 1594th to 1613th, 1595th to 1614th, 1596 1st to 1615th, 1597th to 1616th, 1598th to 1617th, 1599th to 1618th, 1600th to 1619th, 1601st to 1620th, 1602nd to 1621st, 1603rd to 1622nd, 1604th to 1623rd, 1605th to 1624th, 1686th to 170th 5th place, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 1896th, 1878th to 1897th , 1879th to 1898th, 1880th to 1899th, 1881st to 1900th, 1882nd to 1901st, 1883rd to 1902nd, 18 84th to 1903rd, 1885th to 1904th, 1886th to 1905th, 1887th to 1906th, 2093rd to 2112th, 2094 2113th place to 2113th place, 2151st place to 2170th place, 2206th place to 2225th place, 2239th place to 2258th place, 2253rd place to 2272nd place, 2287th place to 2nd 306th place, 2301st to 2320th, 2317th to 2336th, 2337th to 2356th, 2354th to 2373rd, 2387th to 240th 6th place, 2613th to 2632nd, 2614th to 2633rd, 2615th to 2634th, 2616th to 2635th, 2617th to 2636th,2618-2637, 2619-2638, 2620-2639, 2621-2640, 2622-2641, 2623-2642, 2624-2643, 2625-2644, 2626-2645, 2627-2646, 2628 2630-2649, 2631-2650, 2632-2651, 2633-2652, 2634-2653, 2635-2654, 2636-2655, 2637-2656, 2638-2659 7, 2639-2658, 2640-2659, 2641-2660, 2642-2661, 2643-2662, 2644-2663, 2645-2664, 2646-2665, 2647-2666, 2648-2667, 2 649 to 2668, 2663 to 2682, 2672 to 2691, 2673 to 2692, 2674 to 2693, 2675 to 2694, 2676 to 2695, 2677 to 2696, 2678 to 2697, 2679 to 2698, 2680 to 2699, 2681-2700, 2682-2701, 2683-2702, 2684-2703, 2685-2704, 2686-2705, 2687-2706, 2688-2707, 2689-2708, 2690-2709 2691-2710, 2692-2711, 2693-2712, 2694-2713, 2695-2714, 2696-2715, 2697-2716, 2698-2717, 2699-2718, 2700-2719, 2700-2719 1st to 2720th, 2702nd to 2721st, 2703rd to 2722nd, 2704th to 2723rd, 2705th to 2724th, 2706th to 2725th, 2707th to 2726th, 2708th to 2727th, 2709th to 2728th, 2710th to 2729th, 2711th to 2712th 730, 2712-2731, 2713-2732, 2714-2733, 2715-2734, 2716-2735, 2717-2736, 2718-2737, 2719-2738, 2720-2739, 2721-2740,2722nd to 2741st, 2723rd to 2742nd, 2724th to 2743rd, 2725th to 2744th, 2726th to 2745th, 2727th to 2746th, 2728th to 2747th, 2729th to 2748th, 2730th to 2749th, 2731st to 2750th, 2732nd 2751, 2733-2752, 2775-2794, 2790-2809, 2826-2845, 2827-2846, 2828-2847, 2829-2848, 2830-2849, 2831-2850, 2832-285 1, 2833-2852, 2834-2853, 2835-2854, 2836-2855, 2837-2856, 2838-2857, 2839-2858, 2840-2859, 2841-2860, 2842-2861, 2 843 to 2862, 2844 to 2863, 2962 to 2981, 2963 to 2982, 3032 to 3051, 3052 to 3071, 3168 to 3187, 3232 to 3251, 3251 to 3270, 3302 to 3321, 3303 to 3322, 3304-3323, 3305-3324, 3306-3325, 3307-3326, 3308-3327, 3309-3328, 3310-3329, 3311-3330, 3312-3331, 3313-3332 3314-3333, 3315-3334, 3316-3335, 3317-3336, 3318-3337, 3319-3338, 3320-3339, 3321-3340, 3322-3341, 3323-3342, 3324-3343 4th to 3343rd, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3618th to 3637th, 3619th to 3638th, 3620th to 3639th, 3621st to 3640th, 3622nd to 3641st, 3623rd to 3 642, 3624-3643, 3625-3644, 3626-3645, 3627-3646, 3628-3647, 3629-3648, 3630-3649, 3631-3650, 3632-3651, 3633-3652,3634-3653, 3635-3654, 3636-3655, 3637-3656, 3638-3657, 3639-3658, 3640-3659, 3641-3660, 3642-3661, 3643-3662, 3644 3645-3644, 3646-3665, 3647-3666, 3648-3667, 3649-3668, 3650-3669, 3651-3670, 3652-3671, 3653-3672, 3654-367 3, 3671-3690, 3672-3691, 3673-3692, 3674-3693, 3675-3694, 3676-3695, 3677-3696, 3678-3697, 3679-3698, 3680-3699, 3 681 to 3700, 3682 to 3701, 3683 to 3702, 3684 to 3703, 3685 to 3704, 3686 to 3705, 3687 to 3706, 3688 to 3707, 3689 to 3708, 3690 to 3709, 3691 to 3710, 3692-3711, 3693-3712, 3694-3713, 3695-3714, 3696-3715, 3697-3716, 3698-3717, 3699-3718, 3700-3719, 3701-3720 3702-3721, 3703-3722, 3704-3723, 3705-3724, 3706-3725, 3707-3726, 3708-3727, 3709-3728, 3739-3758, 3740-3759, 374 1st to 3760th, 3742nd to 3761st, 3743rd to 3762nd, 3744th to 3763rd, 3745th to 3764th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3965th to 3984th, 3966th to 3985th, 3967th to 3 986, 3968-3987, 3969-3988, 3970-3989, 3971-3990, 3972-3991, 3973-3992, 3974-3993, 3975-3994, 3976-3995, 3977-3996,3978th ​​to 3997th, 3979th to 3998th, 3980th to 3999th, 3981st to 4000th, 3982nd to 4001st, 3983rd to 4002nd, 3984th to 4003rd, 3985th to 4th 004th place, 3986th - 4005th, 3987th - 4006th, 3988th - 4007th, 3989th - 4008th, 3990th - 4009th, 3991st - 4010th, 3992nd - 4011th, 39 93rd to 4012th, 3994th to 4013th, 3995th to 4014th, 3996th to 4015th, 3997th to 4016th, 3998th to 4017th, 3999th to 4018th, 4011th to 403th 0th place, 4177th - 4196th, 4178th - 4197th, 4179th - 4198th, 4180th - 4199th, 4181st - 4200th, 4182nd - 4201st, 4183rd - 4202nd, 4184th ~4203rd place, 4185th place - 4204th place, 4186th place - 4205th place, 4187th place - 4206th place, 4188th place - 4207th place, 4189th place - 4208th place, 4190th place - 4209th place, 4191st place - 4210th place, 4192nd - 4211st, 4193rd - 4212nd, 4194th - 4213th, 4195th - 4214th, 4196th - 4215th, 4197th - 4216th, 4198th - 4217th, 4199th - 42nd The antisense oligonucleotide according to claim 5, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 18, 4200 to 4219, 4201 to 4220, 4202 to 4221, 4203 to 4222, 4204 to 4223, 4205 to 4224, and 4206 to 4225, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

7. positions 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 432, 747 to 778, 965 to 984, 1127 to 1146, 1148 to 1173, 1182 to 1213, 1228 to 1254, 1270 to 1308, 1484 to 1564, 1578 to 1629, 1686 to 1705, 17 48th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1913th, 2015th to 2034th, 2086th to 2118th, 2129th to 2148th, 2151st ~2170th, 2206th ~ 2225th, 2239th ~ 2272nd, 2287th ~ 2336th, 2337th ~ 2373rd, 2387th ~ 2406th, 2598th ~ 2632nd, 2633rd ~ 266th 8th place, 2672nd to 2691st, 2699th to 2757th, 2775th to 2809th, 2826th to 2866th, 2959th to 2978th, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3155th, 3168th to 3187th, 3188th to 3207th, 3232nd to 3270th, 3298th to 3317th, 3325th to 3344th, 3408th to 3427th, 3590 The antisense oligonucleotide according to claim 3, or a pharma- ceutically acceptable salt or hydrate thereof, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 3690 to 3690, 3691 to 3728, 3739 to 3769, 3877 to 3896, 3949 to 3983, 3984 to 4030, and 4170 to 4198.

8. 14 to 33, 34 to 53, 54 to 73, 148 to 167, 397 to 416, 413 to 432, 747 to 766, 756 to 775, 759 to 778, 965 to 984, 1127 to 1146, 1148 to 1167, 1151 to 1170, 1154 to 1173, 1182 to 1201, 1185 to 1204, 1188 to 1207, 1191 to 1210, 1194 to 1213, 1228 to 1247, 1231 to 1250, 1235 to 125 4th place, 1270th to 1289th, 1289th to 1308th, 1484th to 1503rd, 1488th to 1507th, 1491st to 1510th , 1493rd to 1512th, 1506th to 1525th, 1517th to 1536th, 1531st to 1550th, 1545th to 1564th, 1 578th to 1597th, 1586th to 1605th, 1589th to 1608th, 1592nd to 1611th, 1595th to 1614th, 159 8th to 1617th, 1601st to 1620th, 1604th to 1623rd, 1607th to 1626th, 1610th to 1629th, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1870th to 1889th, 1871st to 18th 90th place, 1874th to 1893rd, 1877th to 1896th, 1880th to 1899th, 1883rd to 1902nd, 1886th to 1905th 1889th to 1908th, 1894th to 1913th, 2015th to 2034th, 2086th to 2105th, 2097th to 2116th, 2099th to 2118th, 2129th to 2148th, 2151st to 2170th, 2206th to 2225th, 2239th to 2258th, 225 3rd to 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th to 2336th, 2337th to 2356th, 2354th ~2373rd, 2387th to 2406th, 2598th to 2617th, 2613th to 2632nd, 2633rd to 2652nd, 2649th to 2 668th, 2672nd to 2691st, 2699th to 2718th, 2702nd to 2721st, 2705th to 2724th, 2708th to 272th 7th place, 2711th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2723rd to 2742nd,2726th to 2745th, 2729th to 2748th, 2738th to 2757th, 2775th to 2794th, 2790th to 2809th, 2826th to 2845th, 2829 2848th to 2848th, 2832nd to 2851st, 2835th to 2854th, 2838th to 2857th, 2841st to 2860th, 2847th to 2866th, 2959th to 29th 78th place, 3032nd to 3051st, 3052nd to 3071st, 3136th to 3155th, 3168th to 3187th, 3188th to 3207th, 3232nd to 3251st, 3251st to 3270th, 3298th to 3317th, 3325th to 3344th, 3408th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th ~3636th place, 3635th place - 3654th place, 3654th place - 3673rd place, 3671st place - 3690th place, 3691st place - 3710th place, 3709th place - 3728th place, 3739th place - 375th 8th place, 3750th to 3769th, 3877th to 3896th, 3949th to 3968th, 3964th to 3983rd, 3984th to 4003rd, 3999th to 4018th, 40 The antisense oligonucleotide according to claim 7, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 11 to 4030, positions 4170 to 4189, positions 4173 to 4192, positions 4176 to 4195, and positions 4179 to 4198, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

9. positions 14 to 33, 34 to 53, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1564, 1578 to 1623, 1686 to 1705, 1748 to 1767, 1768 to 1787, and 1794 to 1813 in the base sequence of SEQ ID NO:471 1877th to 1905th, 2151st to 2170th, 2206th to 2225th, 2239th to 2272nd, 2287th to 2336th, 2337th 2373rd to 2373rd, 2387th to 2406th, 2613th to 2632nd, 2633rd to 2668th, 2672nd to 2691st, 2699th to 2748th 8. The antisense oligonucleotide according to claim 5 or 7, or a pharma- ceutically acceptable salt or hydrate thereof, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 2775 to 2809, 2826 to 2860, 3032 to 3051, 3052 to 3071, 3168 to 3187, 3232 to 3270, 3408 to 3427, 3590 to 3690, 3691 to 3728, 3739 to 3758, 3877 to 3896, 3949 to 3983, 3984 to 4030, and 4179 to 4198.

10. positions 14 to 33, 34 to 53, 747 to 766, 1148 to 1167, 1289 to 1308, 1484 to 1503, 1488 to 1507, 1491 to 1510, 1493 to 1512, 1506 to 1525, 1517 to 1536, 1531 to 1550, 1545 to 1564, 1578 to 1597, 1586 to 1605, 1589 to 1608, 1592 to 1611, 1595 to 1614, 1598 to 1617, 1601 to 1620, 1604 to 1623rd, 1686th to 1705th, 1748th to 1767th, 1768th to 1787th, 1794th to 1813th, 1877th to 18th 96th, 1880th to 1899th, 1883rd to 1902nd, 1886th to 1905th, 2151st to 2170th, 2206th to 2225th , 2239th to 2258th, 2253rd to 2272nd, 2287th to 2306th, 2301st to 2320th, 2317th to 2336th, 2 337th to 2356th, 2354th to 2373rd, 2387th to 2406th, 2613th to 2632nd, 2633rd to 2652nd, 2649 2668th to 2668th, 2672nd to 2691st, 2699th to 2718th, 2702nd to 2721st, 2705th to 2724th, 2708th to 2727th, 2711th to 2730th, 2714th to 2733rd, 2717th to 2736th, 2720th to 2739th, 2723rd to 274th 2nd place, 2726th to 2745th, 2729th to 2748th, 2775th to 2794th, 2790th to 2809th, 2826th to 2845th , 2829th to 2848th, 2832nd to 2851st, 2835th to 2854th, 2838th to 2857th, 2841st to 2860th, 30 32nd to 3051st, 3052nd to 3071st, 3168th to 3187th, 3232nd to 3251st, 3251st to 3270th, 3408 3427th to 3427th, 3590th to 3609th, 3608th to 3627th, 3617th to 3636th, 3635th to 3654th, 3654th to 3 673rd, 3671st to 3690th, 3691st to 3710th, 3709th to 3728th, 3739th to 3758th, 3877th to 389th 6th place, 3949th to 3968th, 3964th to 3983rd, 3984th to 4003rd, 3999th to 4018th, 4011th to 4030th,The antisense oligonucleotide according to claim 9, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 4179 to 4198, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

11. The antisense oligonucleotide according to claim 7, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 1598 to 1626, 1870 to 1890, 2097 to 2116, 2711 to 2736, 2841 to 2860, and 4170 to 4198 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

12. The antisense oligonucleotide according to claim 7 or 8, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 1598 to 1617, 1604 to 1623, 1607 to 1626, 1870 to 1889, 1871 to 1890, 2097 to 2116, 2711 to 2730, 2714 to 2733, 2717 to 2736, 2841 to 2860, 4170 to 4189, 4173 to 4192, and 4179 to 4198 of the base sequence of SEQ ID NO: 471, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

13. The antisense oligonucleotide according to any one of claims 1 to 12, which is complementary to a nucleic acid comprising at least 20 consecutive bases of the target region, or a pharma- ceutically acceptable salt or hydrate thereof.

14. (i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 136, 138 to 145, 147 to 158, and 160 to 464. The antisense oligonucleotide according to claim 3 or 4, or a pharma- ceutically acceptable salt or hydrate thereof.

15. (i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14-24, 31-35, 37-40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158, and 163-464; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14-24, 31-35, 37-40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158, and 163-464, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1, 5, 6, 14-24, 31-35, 37-40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158, and 163-464. The antisense oligonucleotide according to claim 5 or 6, or a pharma- ceutically acceptable salt or hydrate thereof.

16. (i) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1 to 4, 6, 8, 9, 11, 14 to 24, 26, 29, 31 to 37, 39 to 50, 52 to 60, 66 to 67, 73 to 75, 79 to 82, 86 to 89, 92 to 111, 115 to 118, 120 to 136, 138 to 145, 147 to 158, and 160 to 163. The antisense oligonucleotide according to claim 7 or 8, or a pharma- ceutically acceptable salt or hydrate thereof.

17. (i) a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14-24, 31-35, 37, 39, 40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158, and 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14-24, 31-35, 37, 39, 40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158, and 163, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1, 6, 14-24, 31-35, 37, 39, 40, 42-45, 47-50, 52-59, 73, 92-100, 103, 107-110, 120-136, 138-143, 150-153, 155-158, and 163. The antisense oligonucleotide according to claim 9 or 10, or a pharma- ceutically acceptable salt or hydrate thereof.

18. (i) a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 98, 100, 101, 104, 105, 116, 131 to 133, 143, 160, 161, and 163. The antisense oligonucleotide according to claim 11 or 12, or a pharma- ceutically acceptable salt or hydrate thereof.

19. (i) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 21, 164 to 222, 233, 234, and 350 to 355. The antisense oligonucleotide according to claim 11 or 12, or a pharma- ceutically acceptable salt or hydrate thereof.

20. (i) a base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199, and 221; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199, and 221, in which one or several bases are added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 170, 177, 196, 199, and 221. The antisense oligonucleotide according to claim 11 or 12, or a pharma- ceutically acceptable salt or hydrate thereof.

21. The antisense oligonucleotide according to any one of claims 14 to 20, or a pharma- ceutically acceptable salt or hydrate thereof, comprising the base sequence of (i).

22. positions 468 to 487, 474 to 493, 583 to 602, 586 to 605, 619 to 638, 770 to 789, 774 to 793, 775 to 794, 778 to 797, 804 to 823, 851 to 870, 1160 to 1179, 1162 to 1181, 1170 to 1189, 1173 to 1192, 1205 to 1224, 1210 to 1229, 1216 to 1235, 1217 to 1236, 1219 to 1238, 1385 to 1390, 1400 to 1401, 1402 to 1402, 1403 to 1403, 1404 to 1404, 1405 to 1405, 1406 to 1406, 1407 to 1407, 1408 to 1409, 1410 to 1414, 1415 to 1416, 1417 to 1418, 1419 to 1420, 1421 to 1422, 1423 to 1424, 1425 to 1426, 1427 to 1428, 1429 to 1430, 1431 to 1432, 1433 to 1434, 1435 to 1436, 1437 to 1438, 1439 to 1440, 1441 to 1442, 144 An antisense oligonucleotide consisting of 15 to 22 nucleotides, which is complementary to a nucleic acid comprising at least 15 consecutive bases in a target region selected from the group consisting of positions 404, 1441 to 1460, 1818 to 1837, 1902 to 1921, 1905 to 1924, 1908 to 1927, 1914 to 1933, 1931 to 1950, 2117 to 2136, 2749 to 2768, 3100 to 3119, and 4125 to 4144, or a pharma- ceutically acceptable salt or hydrate thereof.

23. (i) a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146, and 159; (ii) a base sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146, and 159, in which one or several bases have been added, deleted, or substituted; or (iii) a nucleotide sequence having 90% or more sequence identity to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 7, 10, 12, 13, 25, 27, 28, 30, 61 to 65, 68 to 72, 76 to 78, 83 to 85, 90, 91, 112 to 114, 137, 146, and 159. The antisense oligonucleotide according to claim 22, or a pharma- ceutically acceptable salt or hydrate thereof.

24. The antisense oligonucleotide according to claim 23, or a pharma- ceutically acceptable salt or hydrate thereof, comprising the base sequence of (i).

25. The antisense oligonucleotide according to any one of claims 1 to 24, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the antisense oligonucleotide consists of 20 nucleotides.

26. The antisense oligonucleotide according to any one of claims 1 to 25, wherein the sugar moiety and / or the phosphate linkage moiety of at least one nucleotide constituting the oligonucleotide is modified, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

27. The antisense oligonucleotide of claim 26, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the antisense oligonucleotide is a gapmer comprising a central gap region and two wing regions (5' wing region and 3' wing region) flanking the 5' and 3' ends of the gap region.

28. 28. The antisense oligonucleotide according to claim 27, or a pharma- ceutically acceptable salt or hydrate thereof, wherein all internucleoside bonds are phosphorothioate bonds.

29. The antisense oligonucleotide according to claim 27, or a pharma- ceutically acceptable salt or hydrate thereof, wherein one or more of the bonds between the second and third nucleosides, the bond between the third and fourth nucleosides, and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or one or more of the bonds between the first and second nucleosides, the bond between the second and third nucleosides, and the bond between the third and fourth nucleosides from the 5' side of the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds.

30. The antisense oligonucleotide according to claim 29, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the bond between the second and third nucleosides and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or the bond between the first and second nucleosides and the bond between the third and fourth nucleosides from the 5' side of the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds.

31. The antisense oligonucleotide according to claim 29, or a pharma- ceutically acceptable salt or hydrate thereof, wherein the bonds between the second and third nucleosides, the bond between the third and fourth nucleosides, and the bond between the fourth and fifth nucleosides from the 5' side of the 5' wing region are phosphodiester bonds, and / or the bonds between the first and second nucleosides, the bond between the second and third nucleosides, and the bond between the third and fourth nucleosides from the 5' side of the 3' wing region are phosphodiester bonds, and all other internucleoside bonds are phosphorothioate bonds.

32. The wing region is 2'-OMe (2'-O-CH 3 ) group and / or 2'-O-MOE (2'-O-CH 2 CH 2 OCH 3 32. The antisense oligonucleotide according to any one of claims 27 to 31, or a pharma- ceutically acceptable salt or hydrate thereof, comprising a 2-amino-1-methyl-2-propanediol group.

33. A pharmaceutical composition comprising the antisense oligonucleotide according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, or a hydrate thereof.

34. The antisense oligonucleotide according to any one of claims 1 to 32, or a pharma- ceutical acceptable salt or hydrate thereof, or the pharmaceutical composition according to claim 33, for treating and / or preventing dentatorubral-pallidoluysian atrophy (DRPLA).

35. A method for treating and / or preventing dentatorubral-pallidoluysian atrophy (DRPLA), comprising a step of administering to a subject the antisense oligonucleotide according to any one of claims 1 to 32, or a pharma- ceutical acceptable salt or hydrate thereof, or the pharmaceutical composition according to claim 33 or 34.

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