ATN1 antisense oligonucleotides

Abstract

To provide an antisense oligonucleotide capable of controlling the expression of ATN1 (Atrophin1) gene and treating dentatorubral-pallidoluysian atrophy (DRPLA).SOLUTION: A compound or a pharmaceutically acceptable salt thereof comprising a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence comprising at least 8 consecutive nucleobases that are complementary to the transcript of ATN1. The medicine for treating, preventing and / or improving diseases or conditions against which the inhibitory action on ATN1 gene expression is effective contains the pharmacologically acceptable salts as active ingredients.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to antisense oligonucleotides of ATN1. [Background technology]

[0002] Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar degeneration characterized by lesions in the dentate nucleus, red nucleus, globus pallidus, and corpus Luys. It is caused by an abnormal expansion of CAG repeats in the ATN1 gene. DRPLA is a progressive disorder that manifests as ataxia, myoclonus, epilepsy, and progressive intellectual decline in children, and ataxia, choreoathetosis, dementia, and personality changes in adults. The age of onset ranges from under one year of age to the seventies, with a mean age of 31.5 years. The severity of clinical symptoms is known to correlate with the number of CAG repeats (see, for example, Non-Patent Document 1). Substances that inhibit the expression of the ATN1 gene include RNase H-independent antisense oligonucleotides against CAG repeats (see, for example, Non-Patent Document 2) and ss-siRNA (see, for example, Patent Document 1 and Non-Patent Document 3), which have been shown to selectively inhibit alleles with abnormally expanded repeats. Furthermore, morpholino nucleic acids or RNase H-dependent LNA gapmers have been reported to inhibit the expression of the ATN1 gene, but their sequences and the extent of inhibition are not described (see, for example, Non-Patent Document 4). [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2015 / 017675 [Non-patent literature]

[0004] [Non-Patent Document 1] Movement Disorders, 2010 Aug 15, 25(11), pp 1694-700 [Non-patent document 2] PLoS One, 2011, 6(9), e24308. [Non-patent document 3] Biochemistry, 2014 Jul 22, 53(28), pp 4510-8 [Non-patent document 4] The 38th Annual Meeting of the Japan Neuroscience Society 2015 2P107 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a novel antisense oligonucleotide that inhibits the expression of the ATN1 gene. [Means for solving the problem]

[0006] The present inventors conducted extensive research to find compounds that have antisense effects on ATN1, and discovered that the compounds of the present invention have excellent inhibitory effects on the expression of the ATN1 gene, thereby completing the present invention. That is, the present invention is characterized as follows.

[0007] 1. A compound comprising a modified oligonucleotide consisting of 8 to 80 nucleosides and having a nucleic acid base sequence containing at least 8 consecutive nucleic acid bases of any one of the nucleic acid base sequences of SEQ ID NOs: 3 to 716 and 718 to 770 (3 to 487, 488 to 716, and 718 to 770), or a pharmacologically acceptable salt thereof. 2. The compound according to 1. or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide having a nucleic acid base sequence comprising any one of the nucleic acid base sequences of SEQ ID NOs: 3 to 716 and 718 to 770 (3 to 487, 488 to 716 and 718 to 770). 3. The compound according to 1. or 2., or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide having any one of the nucleic acid base sequences of SEQ ID NOs: 3 to 716 and 718 to 770 (3 to 487, 488 to 716 and 718 to 770).

[0008] 4. Nucleic acid base positions of SEQ ID NO: 1: 59 to 104, 109 to 133, 173 to 192, 207 to 272, 300 to 319, 353 to 372, 419 to 434, 458 to 509, 523 to 559, 561 to 618, 626 to 685, 766 to 785, 787 to 819, 838 to 855, 880 to 922, 924 to 943, 970 to 989, 994 to 1039, 1055 to 1074, 107 9~1098, 1157~1176, 1196~1223, 1310~1329, 1339~1399, 1423~1442, 1614~1633, 1650~1670, 1806~1833, 1844~1865, 1896~1915, 1924~1992, 2023~2042, 2058~2081, 2103~2124, 2398~2417, 2480~2520, 2526~ 2562, 2568~2587, 2853~2872, 2876~2923, 2931~2950, ​​2972~3016, 3072~3099, 3109~3128, 3192~3211, 3267~3290, 3333~3379, 3419~3557, 3765~3784, 3789~3853, 3888~3926, 4022~4062, 4118~4139, 4141~41 A compound or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by SEQ ID NO: 1, wherein the modified oligonucleotide is at least 80% complementary to a portion of the selected nucleic acid base sequence.

[0009] 5. 4. The compound or pharmacologically acceptable salt thereof according to 4., comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of the nucleic acid base sequence represented by positions 3419 to 3557 of the nucleic acid bases in SEQ ID NO: 1, wherein the modified oligonucleotide is at least 80% complementary to a portion of the nucleic acid base sequence represented by positions 3419 to 3557 of the nucleic acid bases in SEQ ID NO: 1.

[0010] 6. Nucleic acid base position numbers 383 to 398, 986 to 1001, 1004 to 1019, 1378 to 1393, 1398 to 1413, 1853 to 1868, 1971 to 1986, 2189 to 2204, 2522 to 2537, 2562 to 2577, 3662 to 3677, 3987 to 4002, 4217 to 4232, 4266 to 4281, 4335 to 4350, 4360 to 4375, 4477 to 4492, 4562 to 4577, 4636 to 4651, 4687 to 4702, 4734 to 4749, 4840 to 4855, 5536 to 5563, 5568 ~5592, 5632~5651, 5666~5715, 5906~5925, 5959~5978, 6176~6191, 6215~6266, 6963~6978, 7248~7284, 7286~7343, 7351-7410, 7491~7510, 7512~75 44, 7563~7580, 7605~7647, 7649~7668, 7695~7714, 7719~7764, 7780~7799, 7804~7823, 7882~7901, 7921~7948, 8035~8054, 8064~8124, 8148~8167, 8 339~8358, 8375~8395, 8531~8558, 8569~8590, 8621~8640, 8649~8717, 8748~8767, 8783~8806, 8828~8849, 9123~9142, 9205~9245, 9336~9351, 9534 ~9570, 9576~9595, 9923~9938, 10001~10016, 10056~10071, 10274~10293, 10297~10344, 10352~10371, 10393~10437, 10493~10520, 10530~10549, 1 a compound comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by 0613 to 10632, 10688 to 10711, 10754 to 10800, 10840 to 10865, 12508 to 12680, 12723 to 12738, 13454 to 13518, 13553 to 13591, 13687 to 13727, 13783 to 13804, 13806 to 13821, 13883 to 13901, and 13931 to 13946, wherein the modified oligonucleotide isA compound or a pharmacologically acceptable salt thereof that is at least 80% complementary to a portion of the selected nucleic acid base sequence of SEQ ID NO: 2.

[0011] 7. Nucleic acid base position numbers 5536 to 5563, 5568 to 5592, 5632 to 5651, 5666 to 5715, 5906 to 5925, 5959 to 5978, 6176 to 6191, 6215 to 6266, 7248 to 7284, 7286 to 7343, 7351 to 7410, 7491 to 7510, 7512 to 7544, 7563 to 7580, 7605 to 7647, 7649 to 7668, 7695 to 7714, 7719 to 7720, 764, 7780~7799, 7804~7823, 7882~7901, 7921~7948, 8035~8054, 8064~8124, 8148~8167, 8339~8358, 8375~8395, 8531~8558, 8569~8590, 8621~8640, 8649~8717, 8748~8767, 8783~8806, 8828~8849, 9123~9142, 9205~9245, 9534~957 0, 9576~9595, 10274~10293, 10297~10344, 10352~10371, 10393~10437, 10493~10520, 10530~10549, 10613~10632, 10688~10711, 10754~10800, 10840~10865, 12572~12680, 13454~13518, 13553~13591, 13687~13727, 13783~13804 13806-13821, 13883-13901, and 13931-13946, wherein the modified oligonucleotide is at least 80% complementary to a portion of the selected nucleic acid base sequence of SEQ ID NO: 2, or a pharmacologically acceptable salt thereof.

[0012] 8. A compound or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 4320 to 4390 and 12508 to 12680 of SEQ ID NO: 2, wherein the modified oligonucleotide is at least 80% complementary to a portion of the selected nucleic acid base sequence of SEQ ID NO: 2.

[0013] 9. A compound according to 6. or 7., or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base position numbers 10840 to 10865 and 12572 to 12680 of SEQ ID NO: 2, wherein the modified oligonucleotide is at least 80% complementary to a portion of the selected nucleic acid base sequence of SEQ ID NO: 2.

[0014] 10. SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 99, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 03, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 2 34, 235, 236, 238, 239, 240, 241, 242, 247, 248, 253, 254, 255, 256, 258, 259, 263, 264, 274, 276, 277, 278, 280, 281, 283, 286, 287, 288, 291, 292, 293, 294 4, 296, 297, 298, 299, 300, 302, 303, 304, 305, 306, 307, 309, 310, 311, 313, 314, 315, 316, 317, 319, 320, 321, 323, 324, 325, 326, 327, 328, 329, 330, 331 , 332, 333, 335, 337, 338, 339, 340, 341, 342, 344, 345, 346, 347, 348, 349, 350, 355, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 369, 371, 372,373, 374, 375, 376, 377, 378, 379, 380, 382, ​​392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441 1, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 494, 513, 515, 533, 534, 544, 545, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 49 51, 552, 554, 566, 574, 582, 585, 586, 589, 592, 593, 595, 596, 638, 639, 642, 644, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 696, 697, 699, 706, 713, 715, 716, 722, 723, 724, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740 741, 742, 743, 744, 745, 746, 748, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, and 770, or a pharmacologically acceptable salt thereof.

[0015] 11. SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 99, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 03, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 2 34, 235, 236, 238, 239, 240, 241, 242, 247, 248, 253, 254, 255, 256, 258, 259, 263, 264, 274, 276, 277, 278, 280, 281, 283, 286, 287, 288, 291, 292, 293, 294 4, 296, 297, 298, 299, 300, 302, 303, 304, 305, 306, 307, 309, 310, 311, 313, 314, 315, 316, 317, 319, 320, 321, 323, 324, 325, 326, 327, 328, 329, 330, 331 , 332, 333, 335, 337, 338, 339, 340, 341, 342, 344, 345, 346, 347, 348, 349, 350, 355, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 369, 371, 372,373, 374, 375, 376, 377, 378, 379, 380, 382, ​​392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 17, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, and 487, or a pharmacologically acceptable salt thereof.

[0016] 12. SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 99, 101, 102, 103, 104, 105, 106, 107, 108, 109, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 24 09, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 1 76, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, 241, 488, 489, 490, 491, 492, 494, 513, 515, 533, 534, 544, 551, 552, 554, 566, 574, 582, 585, 586, 589, 592, 593, 595, 596, 638, 639, 642, 644, 661, 662, 663, 664, 665, 666, 667, 668, 669,670, 671, 672, 673, 674, 675, 676, 677, 696, 697, 699, 706, 713, 715, 716, 722, 723, 724, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 748, 750, 751, 752, 753, The compound according to any one of 1. to 11., or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 12 to 80 nucleosides having a nucleic acid base sequence containing any one nucleic acid base sequence selected from the group consisting of 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, and 770.

[0017] 13. SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 99, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 15 6, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170 , 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, The compound according to any one of 1. to 12., or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 12 to 80 nucleosides having a nucleic acid base sequence comprising any one nucleic acid base sequence selected from the group consisting of 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240 and 241.

[0018] 14. SEQ ID NOs: 242, 247, 248, 253, 254, 255, 256, 258, 259, 263, 264, 274, 276, 277, 278, 280, 281, 283, 286, 287, 288, 291, 292, 293, 294, 296, 297, 298, 299, 300, 302, 303, 304, 305, 306, 307, 309, 310, 311, 313, 314, 315, 316, 317, 319, 320, 321, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 9, 330, 331, 332, 333, 335, 337, 338, 339, 340, 341, 342, 344, 345, 346, 347, 348, 349, 350, 355, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 369, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, ​​392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 9, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, and 487, or a pharmacologically acceptable salt thereof.

[0019] 15. 15. The compound or pharmacologically acceptable salt thereof according to any one of 1. to 14., wherein the modified oligonucleotide contains a phosphorothioate bond. 16. The compound or pharmacologically acceptable salt thereof according to any one of 1. to 15., wherein the modified oligonucleotide comprises at least one nucleoside selected from the group consisting of 2'-modified nucleosides and 2'-4'-bridged nucleosides. 17. 17. The compound or pharmacologically acceptable salt thereof according to 16., wherein the 2'-4'-bridged nucleoside is at least one selected from the group consisting of LNA, ENA, cEt, AmNA, scpBNA, and GuNA. 18. 18. The compound or pharmacologically acceptable salt thereof according to 17., wherein the 2'-4'-bridged nucleoside is LNA. 19. The compound or pharmacologically acceptable salt thereof according to any one of 16 to 18, wherein the 2'-modified nucleoside is at least one selected from the group consisting of a 2'-O-MCE nucleoside, a 2'-O-MOE nucleoside, a 2'-O-NMA nucleoside, and a 2'-O-Me nucleoside.

[0020] 20. 19. The compound or pharmacologically acceptable salt thereof according to 19., wherein the 2'-modified nucleoside is at least one selected from the group consisting of 2'-O-MCE nucleosides and 2'-O-MOE nucleosides. twenty one. The compound or pharmacologically acceptable salt thereof according to any one of 1. to 20., wherein the modified oligonucleotide contains 5-methylcytosine. twenty two. the modified oligonucleotide comprises a gap segment, a 5' wing segment, and a 3' wing segment; the gap segment comprises at least two deoxyribonucleosides, and the 5' and 3' ends of the gap segment are deoxyribonucleosides; the 3'-terminal nucleoside of the 5' wing segment is a sugar-modified nucleoside and is linked to the 5'-terminal of the gap segment; The compound or pharmacologically acceptable salt thereof according to any one of 1. to 21., wherein the 5'-terminal nucleoside of the 3' wing segment is a sugar-modified nucleoside and is linked to the 3'-terminal of the gap segment. twenty three. the gap segment consists of 5 to 30 deoxyribonucleosides, the 5' wing segment and the 3' wing segment each independently consist of 1 to 10 sugar-modified nucleosides independently selected from the group consisting of LNA, 2'-O-MCE nucleosides, and 2'-O-MOE nucleosides; each wing segment comprises at least one phosphorothioate linkage; 23. The compound or pharmacologically acceptable salt thereof according to 22., wherein each cytosine in the gap segment and each wing segment is replaced with 5-methylcytosine. twenty four. the gap segment consists of 8 to 12 deoxyribonucleosides, the 5' wing segment and the 3' wing segment each independently consist of 2 to 5 sugar-modified nucleosides independently selected from the group consisting of LNA and 2'-O-MCE nucleosides, and each include at least one 2'-O-MCE nucleoside; 24. The compound or a pharmacologically acceptable salt thereof according to 23., wherein the gap segment contains at least one phosphorothioate bond.

[0021] twenty five. the gap segment consists of 8 to 12 deoxyribonucleosides, the 5' wing segment and the 3' wing segment each independently consist of 3 to 6 sugar-modified nucleosides selected from the group consisting of 2'-O-MOE nucleosides and 2'-O-MCE nucleosides; 24. The compound or a pharmacologically acceptable salt thereof according to 23., wherein the gap segment contains at least one phosphorothioate bond. 26. 26. The compound or pharmacologically acceptable salt thereof according to 25., wherein the 5' wing segment and the 3' wing segment each independently consist of five 2'-O-MOE nucleosides. 27. 26. The compound or pharmacologically acceptable salt thereof according to 25., wherein the 5' wing segment and the 3' wing segment each independently consist of five 2'-O-MCE nucleosides. 28. 25. The compound or pharmacologically acceptable salt thereof according to 24., wherein the 5' wing segment and the 3' wing segment are each independently selected from the group consisting of VLL, LVL, LLV, LVV, VLV, VVL, LLL, VVLL, VLVL, VLLV, LVLV, LLVV, LVVL, VLLL, LVLL, LLVL, LLLV, LVVV, VLVV, VVLV, and VVVL, wherein L represents LNA and V represents a 2'-O-MCE nucleoside. 29. 25. The compound or pharmacologically acceptable salt thereof according to 24., wherein the 5' wing segment and the 3' wing segment are each independently selected from the group consisting of VLL, LVL, LLV, LVV, VLV, VVL, VVLL, VLVL, LVLV, LLVV, VLLL, LVLL, LLVL, LLLV, LVVV, VLVV, VVLV, and VVVL, wherein L represents LNA and V represents a 2'-O-MCE nucleoside. 30. The compound or pharmacologically acceptable salt thereof according to any one of 1. to 29., wherein the modified oligonucleotide consists of 15 to 25 nucleosides.

[0022] 31. The compound or pharmacologically acceptable salt thereof according to any one of 1. to 30., wherein the modified oligonucleotide is an antisense oligonucleotide. 32. The compound comprising the modified oligonucleotide is the compound according to any one of 1. to 31., or a pharmacologically acceptable salt thereof, which comprises a prodrug moiety. 33. The compound comprising the modified oligonucleotide is the compound according to any one of 1. to 32., or a pharmacologically acceptable salt thereof, which comprises a functional molecule. 34. The compound according to any one of 1. to 33., or a pharmacologically acceptable salt thereof, which consists of the modified oligonucleotide. 35. The salt according to any one of 1. to 34., wherein the pharmacologically acceptable salt is a sodium salt.

[0023] 36. A pharmaceutical comprising, as an active ingredient, the compound or pharmacologically acceptable salt thereof according to any one of 1. to 35. 37. A therapeutic, preventive and / or ameliorating agent for a disease or condition for which inhibiting the expression of the ATN1 gene is effective, comprising as an active ingredient a compound or a pharmacologically acceptable salt thereof according to any one of 1. to 35. 38. An inhibitor of ATN1 gene expression, comprising the compound or pharmacologically acceptable salt according to any one of 1. to 35. as an active ingredient. 39. A drug for treating, preventing, and / or improving dentatorubral-pallidoluysian atrophy, comprising as an active ingredient the compound or pharmacologically acceptable salt thereof according to any one of 1. to 35. [Effects of the Invention]

[0024] The present invention provides a novel antisense oligonucleotide that has an excellent inhibitory effect on the expression of the ATN1 gene and is particularly useful for treating, ameliorating and / or preventing dentatorubral-pallidoluysian atrophy. DETAILED DESCRIPTION OF THE INVENTION

[0025] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. In this description, antisense oligonucleotides may also be referred to as "ASOs."

[0026] Nucleic acids in nature are most basically composed of adenosine (A), thymidine (T) (or uridine (U)), cytidine (C), and guanosine (G). These basic nucleic acids are often referred to as AT(U)GC, etc. Therefore, in this specification, when a sequence is represented as a "nucleic acid base sequence" or "SEQ ID NO:" with respect to, for example, the sequence of the ATN1 gene, it is basically a sequence of A, T, G, C, and U. The nucleic acids constituting the ASO of the present invention include not only basic nucleic acids (AT(U)CG) but also those that have undergone structural modifications. The modifications are described in detail below, but include modifications to the sugar moiety, internucleoside linkage, and / or nucleic acid base. Therefore, in this specification, for example, when an ASO of the present invention is described as a "compound" or a "compound assigned a compound number (M-number and L-number)," and the nucleic acid base sequence is described using A, T, G, C, and U, A, T, G, C, and U also include those that have been structurally modified.

[0027] The present invention will be described in more detail below. Unless otherwise indicated, the following terms have the following meanings.

[0028] "Optionally substituted" means unsubstituted or substituted.

[0029] "Nucleoside" is a term well known to those skilled in the art and is generally understood to mean a molecule in which a sugar and a nucleic acid base are bound, and which can be a unit constituting a nucleic acid. In this specification, nucleoside is a broader concept and includes deoxyribonucleosides, ribonucleosides, and sugar-modified nucleosides, which will be described later. The nucleic acid base may be modified.

[0030] "Deoxyribonucleoside" refers to a molecule having a nucleobase at the 1' carbon atom of 2'-deoxyribose. The deoxyribonucleoside of the present invention may be a naturally occurring deoxyribonucleoside or a deoxyribonucleoside in which the nucleobase portion of a naturally occurring deoxyribonucleoside has been modified. A single deoxyribonucleoside may be modified by a combination of multiple types. The modified deoxyribonucleosides are described, for example, in Journal of Medicinal Chemistry, 2016, 59, pp. 9645-9667; Medicinal Chemistry Communication, 2014, 5, pp. 1454-1471; Future Medicinal Chemistry, 2011, 3, pp. 339-365; and International Publication No. WO 2018 / 155450.

[0031] "Ribonucleoside" refers to a molecule having a nucleobase at the 1' carbon atom of ribose. The ribonucleoside in the present invention may be a naturally occurring ribonucleoside or a ribonucleoside in which the nucleobase moiety of a naturally occurring ribonucleoside has been modified. A single ribonucleoside may be modified by combining multiple types of modifications. The modified ribonucleosides are described, for example, in Journal of Medicinal Chemistry, 2016, 59, pp. 9645-9667; Medicinal Chemistry Communication, 2014, 5, pp. 1454-1471; Future Medicinal Chemistry, 2011, 3, pp. 339-365; and International Publication No. WO 2018 / 155450.

[0032] "Modified sugars" are (Z1) A molecule in which ribose or 2'-deoxyribose is partially replaced by one or more substituents; (Z2) pentose or hexose sugars other than ribose and 2'-deoxyribose (e.g., hexitol, threose, etc.); (Z3) A molecule in which the entire ribose or 2'-deoxyribose, or the tetrahydrofuran ring thereof, is replaced with a 5- to 7-membered saturated or unsaturated ring (e.g., cyclohexane, cyclohexene, morpholine, etc.), or a partial structure capable of forming a 5- to 7-membered ring by hydrogen bonding (e.g., a peptide structure), or (Z4) Molecules in which ribose or 2'-deoxyribose is replaced with alkylene glycol having 2 to 6 carbon atoms (e.g., ethylene glycol, propylene glycol, etc.) means. Modified sugars include "2'-modified sugars" and "2'-4'-linked sugars" described below. Modified sugars and sugar-modified nucleosides described below include, for example, sugars and sugar-modified nucleosides disclosed as being suitable for use in antisense methods in JP 10-304889 A, WO 2005 / 021570 A, JP 10-195098 A, JP 2002-521310 A, WO 2007 / 143315 A, WO 2008 / 043753 A, WO 2008 / 029619 A, WO 2008 / 049085 A, and WO 2017 / 142054 A (hereinafter, these documents are referred to as "documents related to antisense methods"), etc. Modified sugars and sugar-modified nucleosides are also disclosed in Journal of Medicinal Chemistry, 2016, 59, pp. 9645-9667; Medicinal Chemistry Communication, 2014, 5, pp. 1454-1471; Future Medicinal Chemistry, 2011, 3, pp. 339-365; and WO 2018 / 155450.

[0033] Examples of modified sugars that are partially substituted with one substituent include ribose or 2'-deoxyribose substituted at any position of the sugar moiety with the following (i) or (ii): (I C 1-6 Alkyl group. (ii) halogen atoms, C 1-6Alkoxy group, haloC 1-6 Alkoxy group, mono- or di-C 1-6 C substituted with at least one selected from the group consisting of an alkylamino group, a 5- to 10-membered heterocyclic group, a carboxy group, a carbamoyl group, and an N-substituted carbamoyl group 1-6 Alkyl group. Here, examples of the N-substituted carbamoyl group include an N-methyl-carbamoyl group and an N-ethyl-carbamoyl group, and the methyl group and the ethyl group of the N-methyl-carbamoyl group and the N-ethyl-carbamoyl group are 5- to 10-membered heterocyclic groups or mono- or di-C 1-6 It may be substituted with an alkylamino group. Specific examples of the N-substituted carbamoyl group include an N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N-dimethylaminoethyl-carbamoyl group, an N-morpholinoethylcarbamoyl group, an N-(2-pyridylethyl)carbamoyl group, and an N-((benzimidazol-1-yl)ethyl)carbamoyl group.

[0034] "Sugar-modified nucleoside" refers to a molecule having the above-mentioned "modified sugar" instead of the sugar moiety of a deoxyribonucleoside or ribonucleoside. For example, it includes the "2'-modified nucleoside" and "2'-4'-bridged nucleoside" described below. When the modified sugar is (Z3) as defined above, the sugar-modified nucleoside also includes a molecule in which the modified sugar and the nucleobase are linked via a methylene chain or the like.

[0035] "2'-modified sugar" means a non-bridged sugar in which the oxygen atom or carbon atom at the 2' position of ribose is modified, and includes "2'-O-Me," "2'-O-MOE," "2'-O-MCE," "2'-O-NMA," "2'-DMAECE," "2'-MoreECE," "2'-PyECE," and "BimECE." "2'-modified nucleoside" refers to a molecule having a nucleobase at the 1' position of the 2'-modified sugar, and includes, for example, "2'-O-Me nucleoside," "2'-O-MOE nucleoside," "2'-O-MCE nucleoside," "2'-O-NMA nucleoside," "2'-DMAECE nucleoside," "2'-MorECE nucleoside," "2'-PyECE nucleoside," and "BimECE nucleoside."

[0036] "2'-O-Me" (also known as 2'-O-methyl) refers to a sugar in which the 2' hydroxy group of the ribose has been replaced with a methoxy group. A "2'-O-Me nucleoside" (also called a 2'-O-methyl nucleoside) refers to a molecule having a nucleobase at the 1' position of "2'-O-Me."

[0037] "2'-O-MOE" (also known as 2'-O-methoxyethyl) refers to a sugar in which the 2' hydroxy group of ribose has been replaced with a 2-methoxyethyloxy group. A "2'-O-MOE nucleoside" (also called a 2'-O-methoxyethyl nucleoside) refers to a molecule having a nucleobase at the 1' position of "2'-O-MOE."

[0038] "2'-O-MCE" (also known as 2'-O-methylcarbamoylethyl) refers to a sugar in which the hydroxy group at the 2' position of the ribose has been replaced with a methylcarbamoylethyloxy group. "2'-O-MCE nucleoside" (also referred to as 2'-O-methylcarbamoylethyl nucleoside) refers to a molecule having a nucleobase at the 1' position of "2'-O-MCE."

[0039] "2'-O-NMA" means a sugar in which the hydroxy group at the 2' position of ribose has been replaced with a [2-(methylamino)-2-oxoethyl]oxy group. "2'-O-NMA nucleoside" means a molecule having a nucleobase at the 1' position of "2'-O-NMA."

[0040] "2'-AP" ("2'-O-AP") refers to a sugar in which the 2' hydroxy group of the ribose has been replaced with a 3-aminopropyloxy group. A "2'-AP nucleoside" ("2'-O-AP nucleoside") refers to a molecule having a nucleobase at the 1' position of "2'-AP".

[0041] "2'-F" means a sugar in which the 2' hydroxy group of ribose is replaced with a fluorine atom. "2'-F nucleoside" means a molecule having a nucleobase at the 1' position of "2'-F".

[0042] "2'-DMAECE" is a modified sugar having the following structure: [ka]

[0043] "2'-MorECE" is a modified sugar having the following structure: [ka]

[0044] "2'-PyECE" is a modified sugar having the following structure: [ka]

[0045] "BimECE" is a modified sugar having the following structure: [ka]

[0046] "2'-DMAECE nucleoside," "2'-MorECE nucleoside," "2'-PyECE nucleoside," and "BimECE nucleoside" refer to molecules having a nucleobase at the 1' position of "2'-DMAECE," "2'-MorECE," "2'-PyECE," and "BimECE," respectively.

[0047] "2'-4'-linked sugar" refers to a sugar in which the linking unit is replaced by two substitutions at the 2' and 4' positions of the ribose. Examples of the linking unit include C 2-6 an alkylene group (the alkylene group is unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, an oxo group, and a thioxo group, and one or two methylene groups of the alkylene group are unsubstituted or independently substituted with -O-, -NR 1 -(R 1 is a hydrogen atom, C 1-6 Alkyl or haloC 1-6 and -S-, which represents an alkyl group.

[0048] The term "2'-4' bridged nucleoside" (2',4'-BNA) refers to a molecule having a nucleic acid base at the 1' position of the 2'-4' bridged sugar. For example, α-L-methyleneoxy (4'-CH2-O-2') BNA or β-D-methyleneoxy (4'-CH2-O-2') BNA, also known as LNA (Locked Nucleic Acid (registered trademark)), ethyleneoxy (4'-(CH2)2-O-2') BNA, also known as ENA, β-D-thio (4'-CH2-S-2') BNA, aminooxy (4'-CH2-ON (R 11 )-2')BNA(R 11 is H or CH3), 2',4'-BNA NC Also called oxyamino (4'-CH2-N(R 12 )-O-2')BNA(R 12 is H or CH3), 2',4'-BNA COC , 3'-amino-2',4'-BNA, 5'-methyl BNA, (4'-CH(CH3)-O-2') BNA, also called cEt, (4'-CH(CHOCH3)-O-2') BNA, also called cMOE-BNA, amide type BNA (4'-C(=O)-N(R 13 )-2')BNA(R 13is H or CH), also called scpBNA (4'-C(spiro-cyclopropyl)-O-2')BNA, also called GuNA (4'-CH2-N(R 14 )-2')BNA(R 14 is C(=NH2 + )NHR 15 and R 15 is H or CH3), other BNAs known to those skilled in the art, etc.

[0049] In the above-mentioned "deoxyribonucleosides," "ribonucleosides," "2'-modified nucleosides," and "2'-4'-bridged nucleosides," the bond between the 1' carbon atom and the nucleic acid base can be an α-glycosidic bond or a β-glycosidic bond, but is usually a β-glycosidic bond.

[0050] "n-" means normal, "s-" means secondary, and "t-" means tertiary.

[0051] "Halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom.

[0052] "C 1-6 The term "alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, an s-butyl group, a t-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group, and an isohexyl group.

[0053] "Haro C 1-6 The "C alkyl group" refers to the "C 1-6 The term "alkyl group" refers to a group in which a hydrogen atom at any position of the "alkyl group" is substituted with one or more of the above-mentioned "halogen atoms."

[0054] "C 1-6The term "alkylene group" refers to a divalent group obtained by removing one hydrogen atom from any position of a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, and examples thereof include a methylene group, an ethylene (ethanediyl) group, a propane-1,3-diyl (trimethylene) group, a propane-2,2-diyl group, a 2,2-dimethyl-propane-1,3-diyl group, a hexane-1,6-diyl (hexamethylene) group, and a 3-methylbutane-1,2-diyl group. "C 2-6 The "alkylene group" refers to the "C 1-6 Among the "alkylene groups," "a straight-chain or branched divalent group having 2 to 6 carbon atoms" means a straight-chain or branched divalent group having 2 to 6 carbon atoms, and examples thereof include the above-mentioned "C 1-6 The same applies to the "alkylene group." "C 2-20 The term "alkylene group" refers to a divalent group obtained by removing one hydrogen atom from any position of a linear or branched saturated hydrocarbon group having 2 to 20 carbon atoms. 8-12 The term "alkylene group" refers to a divalent group formed by removing one hydrogen atom at any position from a linear or branched saturated hydrocarbon group having 8 to 12 carbon atoms.

[0055] "C 2-20 The term "alkenylene group" refers to a divalent group formed by removing one hydrogen atom at any position from a straight-chain or branched unsaturated hydrocarbon group having 2 to 20 carbon atoms and containing at least one double bond.

[0056] "C 1-6 The "alkoxy group" means the group defined above as "C 1-6 "Alkyl" refers to a group in which an "alkyl" is bonded to an oxy group.

[0057] "Haro C 1-6 The "alkoxy group" means the group defined above as "C 1-6 The term "alkoxy group" refers to a group in which a hydrogen atom at any position of the "alkoxy group" is substituted with one or more of the above-mentioned "halogen atoms."

[0058] "Mono- or di-C 1-6 An "alkylamino group" is a group in which one hydrogen atom of an amino group is bonded to one "C 1-6A group in which two hydrogen atoms of an amino group are replaced by "C alkyl groups" or two hydrogen atoms of an amino group are replaced by the same or different "C 1-6 and examples thereof include methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, and N-ethyl-N-methylamino groups.

[0059] The term "5- to 10-membered heterocyclic group" refers to a 5- to 10-membered monocyclic or fused polycyclic aromatic or non-aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring-constituting atoms. Preferable examples of the "5- to 10-membered heterocyclic group" include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, triazinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, azirid ... Examples include xylanyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, oxopyrrolidinyl, imidazolinyl, oxoimidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and thiomorpholinyl.

[0060] The term "oxo group" refers to a group in which an oxygen atom is substituted via a double bond (=O). When an oxo group is substituted for a carbon atom, it combines with the carbon atom to form a carbonyl group. The term "thioxo group" refers to a group in which a sulfur atom is substituted via a double bond (=S). When a thioxo group is substituted for a carbon atom, it combines with the carbon atom to form a thiocarbonyl.

[0061] A "nucleobase" is a purine base or a pyrimidine base, and may be a naturally occurring nucleobase or a modified naturally occurring nucleobase. Naturally occurring nucleobases include adenine (A), guanine (G), thymine (T), cytosine (C), and uracil (U). The "nucleobase" includes naturally occurring nucleobases and the "modified nucleobases" described below.

[0062] Examples of modifications of nucleobases in "modified nucleobases" include halogenation, methylation, ethylation, n-propylation, isopropylation, cyclopropylation, n-butylation, isobutylation, s-butylation, t-butylation, cyclobutylation, hydroxylation, amination, thiolation, demethylation, etc. More specific examples include 5-methylation, 5-fluorolation, 5-bromination, 5-iodination, and N4-methylation of cytosine; 2-thiolation, 5-demethylation, 5-fluorolation, 5-bromination, and 5-iodination of thymine; 2-thiolation, 5-fluorolation, 5-bromination, and 5-iodination of uracil; N6-methylation and 8-bromination of adenine; and N2-methylation and 8-bromination of guanine. Furthermore, examples of modifications of nucleic acid base moieties in nucleosides are disclosed in Journal of Medicinal Chemistry, 2016, 59, pp. 9645-9667, Medicinal Chemistry Communication, 2014, 5, pp. 1454-1471, Future Medicinal Chemistry, 2011, 3, pp. 339-365, WO 2018 / 155450, and the like.

[0063] The nucleic acid base in the nucleoside is preferably at least one selected from the group consisting of adenine, guanine, thymine, cytosine, uracil and 5-methylcytosine.

[0064] "5-methylcytosine" means a cytosine with a methyl group at the 5-position.

[0065] "Nucleic acid base sequence" means the sequence of nucleic acid bases from the 5' to the 3' end of each nucleoside contained in an oligonucleotide.

[0066] "Contiguous nucleobases" refers to a sequence of contiguous nucleobases from the 5' side to the 3' side in the "nucleobase sequence".

[0067] "Internucleoside linkage" means a group or bond that forms a covalent bond between adjacent nucleosides in an oligonucleotide. "Internucleoside linkage" includes phosphodiester linkages and "modified internucleoside linkages," as defined below.

[0068] The term "modified internucleoside bond" refers to a modified phosphodiester bond, and examples thereof include a phosphorothioate bond, a methylphosphonate bond (including a chiral-methylphosphonate bond), a methylthiophosphonate bond, a phosphorodithioate bond, a phosphoramidate bond, a phosphorodiamidate bond, a phosphoramidothioate bond, and a boranophosphate bond. Examples of modified phosphodiester bonds are disclosed in Journal of Medicinal Chemistry, 2016, 59, pp. 9645-9667; Medicinal Chemistry Communication, 2014, 5, pp. 1454-1471; Future Medicinal Chemistry, 2011, 3, pp. 339-365, etc., and can be used for modified phosphodiester bonds.

[0069] "Modified nucleoside" means a nucleoside having a modified sugar moiety and / or a modified nucleobase.

[0070] An "oligonucleotide" refers to a molecule having a structure in which two or more identical or different "nucleosides" are linked independently of each other by the above-described "internucleoside bond" (e.g., a phosphodiester bond or a modified phosphodiester bond). "Modified oligonucleotide" means an oligonucleotide comprising at least one selected from the group consisting of a modified internucleoside linkage, a modified sugar, and a modified nucleobase. "A compound comprising a modified oligonucleotide" means a compound containing a modified oligonucleotide in its chemical structure, and may be the modified oligonucleotide itself. Examples of compounds comprising a modified oligonucleotide include a compound in which a functional molecule described below is directly or indirectly bound to the modified oligonucleotide, a compound containing a prodrug moiety described below, or the modified oligonucleotide itself.

[0071] "DNA" refers to a polynucleotide or oligonucleotide in which two or more of the same or different "deoxyribonucleosides" are linked by the "internucleoside bond" described above. "RNA" refers to a polynucleotide or oligonucleotide in which two or more of the same or different "ribonucleosides" are linked by the "internucleoside linkage" described above.

[0072] The "antisense effect" refers to the control of the function of a target RNA by hybridizing a target RNA selected corresponding to a target gene with, for example, an oligonucleotide having a sequence complementary to a partial sequence of the target RNA. For example, when the target RNA is mRNA, this refers to the inhibition of translation of the target RNA by hybridization, the effect of converting splicing function such as exon skipping, or the degradation of the target RNA by recognition of the hybridized portion. In the present invention, the target RNA is "ATN1 mRNA" and / or "ATN1 pre-mRNA."

[0073] "Antisense oligonucleotides" (ASOs) are oligonucleotides that produce the antisense effect. Examples include, but are not limited to, DNA, gapmers, and mixmers, and may also include RNA or oligonucleotides designed to normally produce the antisense effect.

[0074] "Hybridize" refers to the act of forming a double strand between oligonucleotides or portions thereof containing complementary sequences, and the phenomenon in which oligonucleotides or portions thereof containing complementary sequences form a double strand.

[0075] "Complementary" means that two nucleobases can form Watson-Crick base pairs (natural base pairs) or non-Watson-Crick base pairs (such as Hoogsteen base pairs) through hydrogen bonds. Two oligonucleotides, or portions thereof, can "hybridize" if their sequences are complementary. Two oligonucleotides, or portions thereof, do not need to be completely complementary to hybridize; however, the degree of complementarity required for two oligonucleotides, or portions thereof, to hybridize is preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more (e.g., 95%, 96%, 97%, 98%, or 99% or more). Sequence complementarity can be determined using a computer program that automatically identifies subsequences of oligonucleotides. For example, OligoAnalyzer is one such software program provided by Integrated DNA Technologies. This program is also available on the website.

[0076] The term "gapmer" refers to an oligonucleotide that includes a "gap segment," a "5' wing segment," and a "3' wing segment," as described below.

[0077] A "gap segment" is a region containing "at least four consecutive nucleosides recognized by RNase H." It is not particularly limited as long as it contains four or more consecutive nucleosides and is recognized by RNase H, but the consecutive nucleosides are preferably independently selected from deoxyribonucleosides and sugar-modified nucleosides. The nucleosides at the 5' and 3' ends of the gap segment are preferably deoxyribonucleosides.

[0078] The "5' wing segment" is a region linked to the 5' side of the gap segment and containing "at least one nucleoside" but excluding the "at least four consecutive nucleosides recognized by RNase H," wherein the sugar moiety of the 3'-terminal nucleoside of the 5' wing segment is different from the sugar moiety of the 5'-terminal nucleoside of the gap segment. The difference in sugar moiety identifies the boundary between the 5' wing segment and the gap segment. (For example, the 5'-terminal nucleoside of the gap segment is a deoxyribonucleoside, and the 3'-terminal nucleoside of the 5' wing segment is a sugar-modified nucleoside.) The 3'-terminal nucleoside of the 5' wing segment is generally a sugar-modified nucleoside. The 5' wing segment is not particularly limited as long as it satisfies the above definition, but the at least one nucleoside is preferably independently selected from a deoxyribonucleoside and a sugar-modified nucleoside, and includes at least one sugar-modified nucleoside. The "3' wing segment" is a region linked to the 3' side of the gap segment and containing "at least one nucleoside" but excluding the "at least four consecutive nucleosides recognized by RNase H," wherein the sugar moiety of the 5'-terminal nucleoside of the 3' wing segment is different from the sugar moiety of the 3'-terminal nucleoside of the gap segment. The difference in sugar moiety identifies the boundary between the 3' wing segment and the gap segment. (For example, the 3'-terminal nucleoside of the gap segment is a deoxyribonucleoside, and the 5'-terminal nucleoside of the 3' wing segment is a sugar-modified nucleoside.) The 5'-terminal nucleoside of the 3' wing segment is generally a sugar-modified nucleoside. The 3' wing segment is not particularly limited as long as it satisfies the above definition, but the at least one nucleoside is preferably independently selected from a deoxyribonucleoside and a sugar-modified nucleoside, and includes at least one sugar-modified nucleoside.

[0079] "RNase H" is generally known as a ribonuclease that recognizes a double-stranded structure formed by hybridizing DNA and RNA in vivo and cleaves the RNA to produce single-stranded DNA. RNase H is not limited to double-stranded structures formed by hybridizing DNA and RNA, but can also recognize double-stranded structures in which at least one of the nucleobase moiety, phosphodiester bond moiety, and sugar moiety of at least one of the DNA and RNA is modified. For example, it can also recognize a double-stranded structure formed by hybridizing DNA modified with phosphorothioate bonds with RNA. Therefore, when DNA hybridizes with RNA, it can be recognized by RNase H. Furthermore, when RNA hybridizes with DNA, it can be cleaved by RNase H. The same applies when at least one of the nucleic acid base moiety, phosphodiester bond moiety, and sugar moiety is modified in at least one of DNA and RNA. For example, a representative example is an oligonucleotide in which the phosphodiester bond moiety of DNA is modified to phosphorothioate. Examples of DNA and / or RNA modifications that can be recognized by RNase H are described, for example, in Nucleic Acids Research, 2014, 42, pp. 5378-5389; Bioorganic & Medicinal Chemistry Letters, 2008, 18, pp. 2296-2300; Molecular BioSystems, 2009, 5, pp. 838-843; Nucleic Acid Therapeutics, 2015, 25, pp. 266-274; The Journal of Biological Chemistry, 2004, 279, pp. 36317-36326, etc. The RNase H used in the present invention is preferably mammalian RNase H, more preferably human RNase H, and particularly preferably human RNase H1.

[0080] The "at least four consecutive nucleosides recognized by RNase H" includes four or more consecutive nucleosides and is not particularly limited as long as it is recognized by RNase H, but examples include "at least four consecutive deoxyribonucleosides." The number of nucleosides constituting the "at least four consecutive nucleosides recognized by RNase H" is, for example, 5 to 30, preferably 5 to 15, more preferably 8 to 12, and particularly preferably 10. Those skilled in the art can determine whether a sequence of at least four consecutive nucleosides is "at least four consecutive nucleosides recognized by RNase H" based on the structure of the sugar moieties of the consecutive nucleosides.

[0081] "ATN1" (Atrophin1) refers to any protein of Atrophin1. "ATN1 mRNA" refers to mRNA encoding the ATN1 protein, and "ATN1 pre-mRNA" refers to pre-mRNA encoding the ATN1 protein. "ATN1 nucleic acid" refers to any nucleic acid encoding ATN1, and includes, for example, "ATN1 mRNA" and "ATN1 pre-mRNA."

[0082] "ATN1 mRNA" is represented, for example, by SEQ ID NO: 1, and "ATN1 pre-mRNA" is represented, for example, by SEQ ID NO: 2 or 717. Both "ATN1 mRNA" and "ATN1 pre-mRNA" have nucleosides linked to each other by phosphodiester bonds, with thymine typically replaced by uracil. "ATN1 mRNA" and "ATN1 pre-mRNA" do not otherwise have modified sugars, modified nucleobases, or modified internucleoside linkages.

[0083] "Gene expression" refers to the conversion of a gene's coding information into structures or functions within a cell, including but not limited to the products of transcription and translation (e.g., mRNA, pre-mRNA, protein, etc.).

[0084] Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant spinocerebellar degeneration characterized by lesions in the dentate nucleus, red nucleus, globus pallidus, and / or corpora Luysiana. DRPLA is known to be caused by an abnormal expansion of CAG repeats in the ATN1 gene. While healthy individuals have 7 to 23 CAG repeats, DRPLA patients have, for example, 49 or more CAG repeats.

[0085] Since the length of the CAG repeat in the ATN1 gene of DRPLA patients varies from patient to patient, antisense oligonucleotides and ss-siRNAs targeting the CAG repeat sequence may have a large variability in efficacy.In addition, since CAG repeats exist in many genes other than ATN1, there is a possibility of off-target effects.The antisense oligonucleotide of the present invention is complementary to ATN1 mRNA and / or ATN1 pre-mRNA and does not target the CAG repeat of the ATN1 gene, i.e., it is complementary to sequences other than the CAG repeat sequence, so it is expected to have small variability in efficacy and small off-target effects. A "CAG repeat sequence" is a sequence in which three base units, cytosine (C), adenine (A), and guanine (G), are repeated in this order. Those skilled in the art can determine from the base sequence of the ASO that a CAG repeat sequence is not a target.

[0086] Next, preferred embodiments of the modified oligonucleotide or compound containing the modified oligonucleotide of the present invention will be described. Note that the following description will be given using an antisense oligonucleotide (ASO) or a compound containing an ASO, which is a preferred example of the modified oligonucleotide or compound containing the modified oligonucleotide, but these descriptions can be applied to the modified oligonucleotide or compound containing the modified oligonucleotide as appropriate. The ASO of the present invention targets ATN1 mRNA or pre-mRNA. The ASO of the present invention does not need to hybridize with the entire ATN1 mRNA or pre-mRNA, but typically hybridizes with at least a portion of it. For example, expression of the ATN1 gene is controlled by hybridization of a portion of the ATN1 mRNA or pre-mRNA with an oligonucleotide (such as a gapmer or an oligonucleotide typically designed to produce an antisense effect) having a sequence complementary to a partial sequence of the ATN1 mRNA or pre-mRNA. Furthermore, the entire ASO does not need to hybridize; a portion may not hybridize.

[0087] The complementarity between the nucleic acid base sequence of the ASO of the present invention and the partial sequence of ATN1 mRNA or pre-mRNA is preferably 70% or more, more preferably 80% or more, and even more preferably 90% or more (e.g., 95%, 96%, 97%, 98%, or 99% or more). In order for the ASO of the present invention to hybridize with at least a portion of the partial sequence of ATN1 mRNA or pre-mRNA, the sequences do not need to be completely complementary, but completely complementary is even more preferable.

[0088] The ASO of the present invention has a gap segment, a 5' wing segment, and a 3' wing segment. The gap segment consists of at least five nucleosides independently selected from the group consisting of deoxyribonucleosides, ribonucleosides, and sugar-modified nucleosides, and the 3'- and 5'-terminus thereof are each independently a deoxyribonucleoside. The gap segment preferably contains "at least four consecutive deoxyribonucleosides."

[0089] The number of nucleosides contained in the gap segment is preferably 5 to 30, more preferably 5 to 15, even more preferably 8 to 12, still more preferably 9 to 11, and particularly preferably 10.

[0090] In some embodiments, the gap segment is composed of deoxyribonucleosides.

[0091] The internucleoside bond contained in the gap segment is preferably at least one type independently selected from a phosphodiester bond and a modified phosphodiester bond, more preferably at least one type independently selected from a phosphodiester bond and a phosphorothioate bond. The internucleoside bond contained in the gap segment preferably contains at least one phosphorothioate bond, more preferably 50% or more phosphorothioate bond, more preferably 75% or more phosphorothioate bond, even more preferably 80% or more phosphorothioate bond, even more preferably 90% or more phosphorothioate bond, and particularly preferably all phosphorothioate bond.

[0092] The 5' wing segment is composed of at least one nucleoside independently selected from the group consisting of deoxyribonucleosides, ribonucleosides, and sugar-modified nucleosides, with the proviso that its 3' end, which is attached to the gap segment, is a sugar-modified nucleoside and does not contain "at least four consecutive nucleosides recognized by RNase H." The 3' wing segment is composed of at least one nucleoside independently selected from the group consisting of deoxyribonucleosides, ribonucleosides, and sugar-modified nucleosides, provided that its 5' end, which is attached to the gap segment, is a sugar-modified nucleoside and does not contain "at least four consecutive nucleosides recognized by RNase H." The 5' wing segment and the 3' wing segment preferably do not contain "at least four consecutive deoxyribonucleosides."

[0093] Hereinafter, the properties common to the 5' wing segment and the 3' wing segment will be referred to as the wing segment. The number of nucleosides contained in each wing segment is 1 to 15, preferably 1 to 10, more preferably 1 to 7, even more preferably 2 to 6, still more preferably 3 to 5, and particularly preferably 3 or 5.

[0094] The sugar-modified nucleosides contained in the wing segments are preferably nucleosides that have increased affinity for a partial sequence of ATN1 mRNA and / or ATN1 pre-mRNA or increased resistance to nucleases due to substitution, etc. More preferably, they are independently selected from 2'-modified nucleosides and 2',4'-BNAs. The 2'-modified nucleoside contained in the wing segment is preferably at least one independently selected from the group consisting of a 2'-O-Me nucleoside, a 2'-O-MOE nucleoside, a 2'-AP nucleoside, a 2'-F nucleoside, a 2'-O-NMA nucleoside, a 2'-O-MCE nucleoside, a 2'-DMAECE nucleoside, a 2'-MorECE nucleoside, a 2'-PyECE nucleoside, and a BimECE nucleoside, more preferably at least one independently selected from the group consisting of a 2'-O-Me nucleoside, a 2'-O-MOE nucleoside, a 2'-O-NMA nucleoside, and a 2'-O-MCE nucleoside, and even more preferably at least one independently selected from a 2'-O-MOE nucleoside and a 2'-O-MCE nucleoside. The 2',4'-BNA contained in the wing segment is preferably LNA, cEt, ENA, BNA NC , AmNA, GuNA and scpBNA, and more preferably LNA. The sugar-modified nucleoside contained in the wing segment is more preferably at least one independently selected from a 2'-O-MOE nucleoside, an LNA, and a 2'-O-MCE nucleoside, even more preferably a 2'-O-MOE nucleoside, a 2'-O-MCE nucleoside, or an LNA and a 2'-O-MCE nucleoside, and particularly preferably a 2'-O-MOE nucleoside or an LNA and a 2'-O-MCE nucleoside.

[0095] Each wing segment preferably consists of 1 to 10 nucleosides independently selected from the group consisting of sugar-modified nucleosides and deoxyribonucleosides, and includes at least one sugar-modified nucleoside. More preferably, each wing segment consists of 2 to 6 nucleosides independently selected from the group consisting of sugar-modified nucleosides and deoxyribonucleosides, and includes at least two sugar-modified nucleosides. Even more preferably, each wing segment consists of 2 to 6 nucleosides independently selected from the group consisting of 2'-modified nucleosides and 2',4'-BNAs, and even more preferably, each wing segment consists of 3 to 5 nucleosides independently selected from the group consisting of 2'-modified nucleosides and 2',4'-BNAs. More specifically, each wing segment is composed of 1 to 10, preferably 2 to 6, more preferably 3 to 5, nucleosides independently selected from LNA, 2'-O-MCE nucleosides, and 2'-O-MOE nucleosides. It is even more preferred that each wing segment is composed of 2 to 5, more preferably 3 to 5, nucleosides independently selected from LNA and 2'-O-MCE nucleosides. Of these, it preferably contains at least one 2'-O-MCE nucleoside, and even more preferably contains at least one LNA and at least one 2'-O-MCE nucleoside. It is even more preferred that each wing segment is composed of two LNAs and one or two 2'-O-MCE nucleosides, and particularly preferred that each wing segment is composed of two LNAs and one 2'-O-MCE nucleoside. In another embodiment, it is preferably composed of 3 to 6, and particularly preferred that each wing segment is composed of five 2'-O-MOE nucleosides. In yet another embodiment, it preferably consists of 3 to 6, and particularly preferably 5, 2'-O-MCE nucleosides. In another preferred embodiment, each wing segment is an oligonucleotide comprising 2 to 5 nucleosides independently selected from the group consisting of 2',4'-BNAs and deoxyribonucleosides, and including at least two 2',4'-BNAs. Such oligonucleotides can be described with reference to International Publication No. WO 2016 / 127002, etc.

[0096] In some embodiments of the invention, the 5' wing segment and the 3' wing segment each independently comprise 3, 4, 5, or 6 sugar-modified nucleosides, and the gap segment consists of 8, 9, 10, 11, 12, 13, or 14 deoxyribonucleosides. The number of nucleosides in such gapmers can be expressed as (5' wing segment-gap segment-3' wing segment), and includes 5-10-5, 5-11-4, 4-11-5, 4-12-4, 3-14-3, 6-8-6, 3-12-3, 3-10-3, 4-10-4, 3-10-4, 4-10-3, 3-9-3, 4-9-4, 3-9-4, 4-9-3, 3-8-3, 3-8-4, 4-8-3, and 4-8-4.

[0097] In some embodiments, the ASO has at least 11, 12, 13, 14, or 15 consecutive nucleosides, the gap segment comprises at least 5, 6, 7, 8, or 9 consecutive nucleosides, and the 5' wing segment and 3' wing segment are any of (i) to (iv) below. (i) the 5' wing segment and the 3' wing segment each independently comprise 3, 4, 5, or 6 2'-O-MOE nucleosides; (ii) the 5' wing segment and the 3' wing segment each independently comprise 3, 4, 5, or 6 2'-O-MCE nucleosides; (iii) the 5' wing segment and the 3' wing segment each independently comprise 2, 3, 4, 5, or 6 LNAs. (iv) the 5' wing segment and the 3' wing segment each independently comprise three or four nucleosides selected from 2'-O-MCE nucleosides and LNAs, and comprise at least one 2'-O-MCE nucleoside and at least one LNA.

[0098] In the ASOs of the invention, the 5' and 3' wing segments are preferably selected from the group consisting of VLL, LVL, LLV, LVV, VLV, VVL, LLL, VVLL, VLVL, VLLV, LVLV, LLVV, LVVL, VLLL, LVLL, LLVL, LLLV, LVVV, VLVV, VVLV, and VVVL. More preferably, it is selected from the group consisting of VLL, LVL, LLV, LVV, VLV, VVL, VVLL, VLVL, VLLV, LVLV, LLVV, LVVL, VLLL, LVLL, LLVL, LLLV, LVVV, VLVV, VVLV, and VVVL. More preferably, it is selected from the group consisting of VLL, LVL, LLV, LVV, VLV, VVL, VVLL, VLVL, LVLV, LLVV, VLLL, LVLL, LLVL, LLLV, LVVV, VLVV, VVLV, and VVVL. More preferably, the 5' wing segment is selected from the group consisting of VLL, VLV, VVL, VVLL, VLVL, VLLL, VLVV, VVLV, and VVVL, and the 3' wing segment is selected from the group consisting of LLV, VLV, LVV, LLVV, LVLV, VLLV, VVLV, VLVV, and LVVV. Even more preferably, the 5' wing segment is selected from the group consisting of VLL, VLV, VVL, and VLVL, and the 3' wing segment is selected from the group consisting of LLV, VLV, LVV, and LVLV. Particularly preferably, the 5' wing segment is a VLL and the 3' wing segment is an LLV. In other embodiments, preferably the 5' wing segment is selected from the group consisting of LLL, VLL, LVL, VVL, LLV, VLVL, LVLV, LLVV and VLLV, and the 3' wing segment is selected from the group consisting of LLL, LLV, LVL, LVV, VLL, LVLV and VLLV. More preferably, the 5' wing segment is selected from the group consisting of VLL, LVL, VVL, LLV, VLVL and VLLV, and the 3' wing segment is selected from the group consisting of LLV, LVL, LVV, VLL, LVLV and VLLV. Here, L and V in the 5' wing segment and the 3' wing segment are sugar-modified nucleosides each having a different modified sugar, with the left side representing the 5' side and the right side representing the 3' side. Preferably, L represents a 2'-4' bridged nucleoside, and V represents a 2'-modified nucleoside. Particularly preferably, L represents LNA, and V represents a 2'-O-MCE nucleoside.

[0099] The internucleoside bond contained in the 5' wing segment is preferably at least one type independently selected from a phosphodiester bond and a modified phosphodiester bond, more preferably at least one type independently selected from a phosphodiester bond and a phosphorothioate bond. The internucleoside bond contained in the 5' wing segment preferably contains at least one phosphorothioate bond, with 50% or more being phosphorothioate bond, preferably 60% or more being phosphorothioate bond, more preferably 75% or more being phosphorothioate bond, even more preferably 80% or more being phosphorothioate bond, even more preferably 90% or more being phosphorothioate bond, and particularly preferably all being phosphorothioate bond. The 3' wing segment is similar to the 5' wing segment.

[0100] In another embodiment, from the viewpoint of reducing toxicity, all of the internucleoside linkages contained in the wing segment may be phosphodiester linkages, but it is preferable that some of them are phosphodiester linkages. The 5'-terminal internucleoside bond in the 5' wing segment is preferably a phosphorothioate bond. The 3'-terminal internucleoside bond in the 3' wing segment is preferably a phosphorothioate bond. The other internucleoside bonds in the 5' wing segment, excluding the 5'-terminal internucleoside bond of the 5' wing segment, may be phosphodiester or phosphorothioate bonds, but preferably 50% or more are phosphodiester bonds, more preferably 60% or more are phosphodiester bonds, even more preferably 75% or more are phosphodiester bonds, even more preferably 80% or more are phosphodiester bonds, even more preferably 90% or more are phosphodiester bonds, and particularly preferably all are phosphodiester bonds. The other internucleoside linkages in the 3' wing segment, excluding the internucleoside linkage at the 3' end of the 3' wing segment, may be phosphodiester linkages or phosphorothioate linkages, but preferably 50% or more are phosphodiester linkages, more preferably 60% or more are phosphodiester linkages, even more preferably 75% or more are phosphodiester linkages, even more preferably 80% or more are phosphodiester linkages, even more preferably 90% or more are phosphodiester linkages, and particularly preferably all are phosphodiester linkages. Of the internucleoside linkages contained in each wing segment, the internucleoside linkage located closest to the gap segment is preferably a phosphodiester linkage.

[0101] For example, when the 5' wing segment contains two internucleoside linkages, the internucleoside linkage at the 5' end is preferably a phosphorothioate linkage, and the internucleoside linkage on the gap segment side is preferably a phosphodiester linkage. When the 5' wing segment contains three internucleoside linkages, the internucleoside linkage at the 5' end is preferably a phosphorothioate linkage, and the other two internucleoside linkages contained in the 5' wing segment are preferably independently phosphodiester or phosphorothioate linkages, with phosphodiester linkages being particularly preferred. When the 5' wing segment contains four internucleoside linkages, the internucleoside linkage at the 5' end is preferably a phosphorothioate linkage, and the other three internucleoside linkages contained in the 5' wing segment are preferably independently phosphodiester or phosphorothioate linkages, with phosphodiester linkages being particularly preferred.

[0102] When the 3' wing segment contains two internucleoside linkages, the internucleoside linkage at the 3' end is preferably a phosphorothioate linkage, and the internucleoside linkage on the gap segment side is preferably a phosphodiester linkage. When the 3' wing segment contains three internucleoside linkages, the internucleoside linkage at the 3' end is preferably a phosphorothioate linkage, and the other two internucleoside linkages contained in the 3' wing segment are preferably independently phosphodiester or phosphorothioate linkages, with phosphodiester linkages being particularly preferred. When the 3' wing segment contains four internucleoside linkages, the internucleoside linkage at the 3' end is preferably a phosphorothioate linkage, and the other three internucleoside linkages contained in the 3' wing segment are preferably independently phosphodiester or phosphorothioate linkages, with phosphodiester linkages being particularly preferred.

[0103] In the ASO of the present invention, the 3' end of the 5' wing segment is preferably linked to the 5' end of the gap segment by a phosphodiester bond or a modified phosphodiester bond, and the 5' end of the 3' wing segment is linked to the 3' end of the gap segment by a phosphodiester bond or a modified phosphodiester bond. More preferably, the 3' end of the 5' wing segment is linked to the 5' end of the gap segment by a modified phosphodiester bond, and the 5' end of the 3' wing segment is linked to the 3' end of the gap segment by a modified phosphodiester bond. Even more preferably, the 3' end of the 5' wing segment is linked to the 5' end of the gap segment by a phosphorothioate bond, and the 5' end of the 3' wing segment is linked to the 3' end of the gap segment by a phosphorothioate bond.

[0104] In another preferred embodiment of the ASO of the present invention, the 3' end of the 5' wing segment is linked to the 5' end of the gap segment by a phosphodiester bond, and the 5' end of the 3' wing segment is linked to the 3' end of the gap segment by a phosphorothioate bond. The present invention includes ASOs in which the 3' end of the 5' wing segment is linked to the 5' end of the gap segment by a phosphorothioate bond and the 5' end of the 3' wing segment is linked to the 3' end of the gap segment by a phosphodiester bond, and also includes ASOs in which the 3' end of the 5' wing segment is linked to the 5' end of the gap segment by a phosphodiester bond and the 5' end of the 3' wing segment is linked to the 3' end of the gap segment by a phosphodiester bond.

[0105] The ASO of the present invention is preferably a nucleic acid sequence encoding a nucleic acid sequence corresponding to nucleic acid bases at positions 59 to 104, 109 to 133, 173 to 192, 207 to 272, 300 to 319, 353 to 372, 419 to 434, 458 to 509, 523 to 559, 561 to 618, 626 to 685, 766 to 785, 787 to 819, 838 to 855, 880 to 922, 924 to 943, 970 to 985, 986 to 990, 992 to 1000, 1000 to 1010, 1010 to 1020, 1020 to 1030, 1030 to 1040, 1040 to 1050, 1050 to 1060, 1060 to 1070, 1070 to 1080, 1080 to 1100, 1100 to 1111, 1110 to 1120, 1120 to 1130, 1130 to 1140, 1140 to 1150, 1150 to 1160, 1160 to 1170, 1170 to 1180, 1180 to 1190, 1200 to 1220, 1220 to 1230, 1240 to 1250, 1260 to 1270, 1280 to 1290, 1300 to 1310, 1310 to 989, 994-1039, 1055-1074, 1079-1098, 1157-1176, 1196-1223, 1310-1329, 1339-1399, 1423-1442, 1614-1633, 1650-1670, 1806-1833, 1844-1865, 1896-1915, 1924-1992, 20 23~2042, 2058~2081, 2103~2124, 2398~2417, 2480~2520, 2526~2562, 2568~2587, 2853~2872, 2876~2923, 2931~2950, ​​2972~3016, 3072~3099, 3109~3128, 3192~3211, 3267~32 90, 3333 to 3379, 3419 to 3557, 3765 to 3784, 3789 to 3853, 3888 to 3926, 4022 to 4062, 4118 to 4139, 4141 to 4156, 4218 to 4236, and 4266 to 4281.

[0106] More preferably, the nucleic acid bases at positions 238 to 272, 537 to 559, 585 to 618, 664 to 683, 787 to 819, 838 to 855, 924 to 943, 972 to 987, 994 to 1029, 1055 to 1074, 1080 to 1095, 1204 to 1219, 1310 to 1329, 1362 to 1397, 1650 to 1670, 1806 to 1833, 1844 to 1865, 1896 to 1915, 1955 to 1992, 2058 to 2081, 2115 to 2116, 2125 to 2130, 2135 to 2131, 2145 to 2150, 2155 to 2162, 2165 to 2170, 2175 to 2176, 2185 to 2187, 2195 to 2200, 2200 to 2213, 2216 to 2217, 2227 to 2230, 2235 to 2231, 2245 to 2242, 2255 to 2260, 2265 to 2271, 2275 to 2272, 2285 to 2286, 2285 to 2287, 2295 to 2300, 2316 to 2317, 2325 to 2329, 2335 to 2336, 2 It is complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by 03 to 2124, 2480 to 2503, 2876 to 2923, 2931 to 2946, 2979 to 3016, 3109 to 3128, 3192 to 3211, 3267 to 3290, 3333 to 3379, 3419 to 3557, 3812 to 3833, 3888 to 3926, 4022 to 4062, 4118 to 4137, 4218 to 4236, and 4266 to 4281. More preferably, it is complementary to a part of the nucleic acid base sequence represented by nucleic acid base positions 3419 to 3557 of the ATN1 mRNA represented by SEQ ID NO:1. Particularly preferred complementary positions to ATN1 mRNA are listed below. It is complementary to a part of the nucleic acid base sequence represented by nucleic acid base positions 3452 to 3467 of the ATN1 mRNA represented by SEQ ID NO:1. It is complementary to a part of the nucleic acid base sequence represented by nucleic acid base positions 3459 to 3474 of the ATN1 mRNA represented by SEQ ID NO:1. It is complementary to a part of the nucleic acid base sequence represented by nucleic acid base positions 3460 to 3475 of the ATN1 mRNA represented by SEQ ID NO:1. It is complementary to a part of the nucleic acid base sequence represented by nucleic acid base positions 3461 to 3476 of the ATN1 mRNA represented by SEQ ID NO:1. It is complementary to a part of the nucleic acid base sequence represented by nucleic acid base positions 3488 to 3503 of the ATN1 mRNA represented by SEQ ID NO:1.

[0107] The complementarity between the ASO of the present invention and the relevant portion of the ATN1 mRNA represented by sequence number 1 (e.g., each of the target regions mentioned above) is at least 80% or more, preferably 85% or more, more preferably 90% or more, and even more preferably 95%, 96%, 97%, 98%, or 99% or more. The ASO of the present invention preferably consists of 8 to 80 nucleosides complementary to a portion of each of the above-mentioned target regions of the ATN1 mRNA represented by SEQ ID NO: 1. It more preferably consists of 10 to 50 nucleosides, even more preferably 16 to 20 nucleosides, and particularly preferably 16 or 20 nucleosides.

[0108] The ASO of the present invention is preferably a nucleic acid sequence selected from the group consisting of nucleic acid bases at positions 383 to 398, 986 to 1001, 1004 to 1019, 1378 to 1393, 1398 to 1413, 1853 to 1868, 1971 to 1986, 2189 to 2204, 2522 to 2537, 2562 to 2577, 3662 to 3677, 3987 to 4002, 4217 to 4232, 4266 to 4281, 4335 to 4350, 4360 to 4375, 4477 to 4492, 4562 to 4577, 4636 to 4651, 4687 to 4702, 4734 to 4749, and 4840 to 4855 of the nucleic acid bases of the ATN1 pre-mRNA represented by SEQ ID NO: 2. , 5536~5563, 5568~5592, 5632~5651, 5666~5715, 5906~5925, 5959~5978, 6176~6191, 6215~6266, 6963~6978, 7248~7284, 7286~7343, 7351-7410, 7491~7510, 7512~7544, 7563~7580, 7605~7647, 7649~7668, 7695~7714, 7719~7764, 7780~7799, 7804~7823, 7882~7901, 7921~7948, 8035 ~8054, 8064~8124, 8148~8167, 8339~8358, 8375~8395, 8531~8558, 8569~8590, 8621~8640, 8649~8717, 8748~8767, 8783~8806, 8828~8849, 9123~9142, 9205~9245, 9336~9351, 9534~9570, 9576~9595, 9923~9938, 10001~10016, 10056~10071, 10274~10293, 10297~10344, 10352~10371 , 10393 to 10437, 10493 to 10520, 10530 to 10549, 10613 to 10632, 10688 to 10711, 10754 to 10800, 10840 to 10865, 12508 to 12680, 12723 to 12738, 13454 to 13518, 13553 to 13591, 13687 to 13727, 13783 to 13804, 13806 to 13821, 13883 to 13901, and 13931 to 13946.

[0109] The ASO of the present invention is preferably a nucleic acid sequence encoding a nucleic acid sequence encoding a nucleic acid sequence of ATN1 pre-mRNA represented by SEQ ID NO: 2, which is selected from the group consisting of nucleic acid sequences of 383 to 398, 986 to 1001, 1004 to 1019, 1378 to 1393, 1398 to 1413, 1853 to 1868, 1971 to 1986, 2189 to 2204, 2522 to 2537, 2562 to 2577, 3662 to 3677, 3987 to 4002, 4217 to 4232, 4266 to 4281, 4335 to 4350, 4360 to 4375, 4477 to 4492, 4562 to 4577, 4636 to 4651, 4687 to 4702, 4734 to 4749, 4840 to 4855, 5555 to 5566, 5571 to 5572, 5581 to 5582, 5591 to 5593, 5594 to 5595, 5596 to 5597, 5598 to 5599, 5601 to 5602, 5603 to 5604, 5605 to 5606, 5606 to 5608, 5609 to 5610, 5611 to 5612, 5613 to 5614, 5615 to 5616, 5617 to 5618, 5618 36~5563, 5568~5592, 5632~5651, 5666~5715, 5906~5925, 5959~5978, 6176~6191, 6215~6266, 6963~6978, 7248~7284, 7286~7343, 7351-7410, 7491~7510, 7512~7544, 7563~7580, 7605~7647, 7649~7668, 7695~7714, 7719~7764, 7780~7799, 7804~7823, 7882~7901, 7921~7948, 8035~8054, 8064~8124, 8148~8167, 8339~8358, 8375~8395, 8531~8558, 8569~8590, 8621~8640, 8649~8717, 8748~8767, 8783~8806, 8828~8849, 9123~9142, 9205~9245, 9336~9351, 9534~9570, 9576~9595, 9923~9938, 10001~10016, 10056~10071, 10274~10293, 10297~10344, 10352~10371, 10393~10 437, 10493 to 10520, 10530 to 10549, 10613 to 10632, 10688 to 10711, 10754 to 10800, 10840 to 10865, 12508 to 12523, 12572 to 12680, 12723 to 12738, 13454 to 13518, 13553 to 13591, 13687 to 13727, 13783 to 13804, 13806 to 13821, 13883 to 13901, and 13931 to 13946.

[0110] The ASO of the present invention preferably comprises a nucleic acid sequence corresponding to nucleic acid base positions 5536 to 5563, 5568 to 5592, 5632 to 5651, 5666 to 5715, 5906 to 5925, 5959 to 5978, 6176 to 6191, 6215 to 6266, 7248 to 7284, 7286 to 7343, 7351 to 7410, 7491 to 7510, 7512 to 7544, 7563 to 7580, 7605 to 7616, and 7627 to 7630 of the ATN1 pre-mRNA represented by SEQ ID NO: 2. 647, 7649~7668, 7695~7714, 7719~7764, 7780~7799, 7804~7823, 7882~7901, 7921~7948, 8035~8054, 8064~8124, 8148~8167, 8339~8358, 8375~8395, 8531~8558, 8569~8590, 8621~8640, 8649~8717, 8748~8767, 8783~8806, 8828~8849, 9123~9142, 9205~9245, 9534~9570, 9576~9595, 10274~10293, 10297~10344, 10352~10371, 10393~10437, 10493~10520, 10530~10549, 10613~10632, 10688~1071 1, 10754-10800, 10840-10865, 12572-12680, 13454-13518, 13553-13591, 13687-13727, 13783-13804, 13806-13821, 13883-13901, and 13931-13946.

[0111] More preferably, the nucleic acid bases at positions 986 to 1001, 1004 to 1019, 1378 to 1393, 1398 to 1413, 4217 to 4232, 4335 to 4350, 4360 to 4375, 4477 to 4492, 4562 to 4577, 4636 to 4651, 4687 to 4702, 4734 to 4749, 4840 to 4855, 5697 to 5711, 5698 to 5712, 5699 to 5713, 5714 to 5715, 5716 to 5717, 5718 to 5719, 5719 to 5719, 5719 to 5719, 5719 to 5719, 5810 to 5810, 5811 to 5811, 5812 to 5812, 5813 to 5814, 5815 to 5815, 5816 to 5816, 5817 to 5817, 5818 to 5819, 5819 to 5820, 5819 to 5821, 5819 to 5822, 5819 to 5823, 5819 to 5824, 5819 to 5825, 5819 to 5826, 5819 to 5827, 5819 to 5828, 5819 to 5829, 5829 to 5830, 5829 to 583 5, 6963~6978, 7262~7284, 7310~7343, 7389~7408, 7512~7544, 7563~7580, 7649~7668, 7697~7712, 7719~7754, 7780~7799, 7805~7820, 7929~7944, 8035~8054, 8087~8122, 8375~8395, 8531 ~8558, 8569~8590, 8621~8640, 8680~8717, 8783~8806, 8828~8849, 9205~9228, 10297~10344, 10352~10367, 10400~10437, 10530~10549, 10613~10632, 10688~10711, 10754~10800, 10840~ It is complementary to a portion of a nucleic acid base sequence selected from the group consisting of the nucleic acid base sequences represented by 10865, 12508-12523, 12572-12680, 12723-12738, 13477-13498, 13553-13591, 13687-13727, 13783-13802, 13883-13901, and 13931-13946.

[0112] More preferably, the nucleic acid bases at positions 5697 to 5715, 7262 to 7284, 7310 to 7343, 7389 to 7408, 7512 to 7544, 7563 to 7580, 7649 to 7668, 7697 to 7712, 7719 to 7754, 7780 to 7799, 7805 to 7820, 7929 to 7944, 8035 to 8054, 8087 to 8122, 8375 to 8395, 8531 to 8558, 8569 to 8590, 8621 to 8640, 8680 to 8717, 8783 to 8806, 8828 to 8849, 92 and is complementary to a portion of a nucleic acid base sequence selected from the group consisting of the nucleic acid base sequences represented by 05-9228, 10297-10344, 10352-10367, 10400-10437, 10530-10549, 10613-10632, 10688-10711, 10754-10800, 10840-10865, 12572-12680, 13477-13498, 13553-13591, 13687-13727, 13783-13802, 13883-13901, and 13931-13946. More preferably, it is complementary to a part of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base position numbers 10840 to 10865 and 12572 to 12680. Particularly preferably, it is complementary to a part of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base position numbers 12572 to 12680.

[0113] In another embodiment, it is preferably complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 4320 to 4390 and 12508 to 12680 of the ATN1 pre-mRNA represented by SEQ ID NO: 2.

[0114] In another embodiment, it is preferably complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 4320 to 4390 of the ATN1 pre-mRNA represented by SEQ ID NO:2.

[0115] In another embodiment, more preferably, it is complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 12508 to 12680 of the ATN1 pre-mRNA represented by SEQ ID NO:2. Particularly preferred complementary positions to the ATN1 pre-mRNA are listed below. It is complementary to a part of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 12575 to 12590 of the ATN1 pre-mRNA represented by SEQ ID NO:2. It is complementary to a part of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 12582 to 12597 of the ATN1 pre-mRNA represented by SEQ ID NO:2. It is complementary to a part of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 12583 to 12598 of the ATN1 pre-mRNA represented by SEQ ID NO:2. It is complementary to a part of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 12584 to 12599 of the ATN1 pre-mRNA represented by SEQ ID NO:2. It is complementary to a part of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 12611 to 12626 of the ATN1 pre-mRNA represented by SEQ ID NO:2.

[0116] The complementarity between the ASO of the present invention and the corresponding portion of the ATN1 pre-mRNA represented by sequence number 2 (e.g., each of the target regions mentioned above) is at least 80% or more, preferably 85% or more, more preferably 90% or more, and even more preferably 95%, 96%, 97%, 98%, or 99% or more. The ASO of the present invention preferably consists of 8 to 80 nucleosides complementary to a portion of each of the above-mentioned target regions of the ATN1 pre-mRNA represented by SEQ ID NO: 2. It more preferably consists of 10 to 50 nucleosides, even more preferably 16 to 20 nucleosides, and particularly preferably 16 or 20 nucleosides.

[0117] The nucleic acid base sequence possessed by the ASO of the present invention preferably contains at least 8, more preferably 8, 9, 10, 11, 12, 13, 14 or 15 consecutive nucleic acid bases of any of the nucleic acid base sequences of SEQ ID NOs: 3 to 716 and 717 to 770 (in one aspect, 3 to 487, 488 to 716, and 717 to 770). The nucleic acid base sequence possessed by the ASO of the present invention more preferably comprises any of the nucleic acid base sequences of SEQ ID NOs: 3 to 716 and 717 to 770 (in one aspect, 3 to 487, 488 to 716, and 717 to 770).

[0118] The nucleic acid base sequence possessed by the ASO of the present invention preferably comprises at least 8, more preferably 8, 9, 10, 11, 12, 13, 14 or 15 consecutive nucleic acid bases of any one of the nucleic acid base sequences in nucleic acid base sequence group A (A1, A2 and A3), and even more preferably comprises any one of the nucleic acid base sequences in nucleic acid base sequence group A (A1, A2 and A3). In another embodiment, more preferably, the nucleic acid has a nucleic acid sequence containing at least 8, more preferably 8, 9, 10, 11, 12, 13, 14 or 15 consecutive nucleic acid bases of any one of the nucleic acid base sequences in nucleic acid base sequence group B (B1, B2 and B3), and even more preferably contains any one of the nucleic acid base sequences in nucleic acid base sequence group B (B1, B2 and B3). In another embodiment, it is more preferred that the nucleic acid sequence contains at least 8 consecutive nucleic acid bases of any one of the nucleic acid base sequences in nucleic acid base sequence group C (C1 and C2), and even more preferred that the nucleic acid sequence contains 8, 9, 10, 11, 12, 13, 14 or 15 consecutive nucleic acid bases, and it is particularly preferred that the nucleic acid sequence contains any one of the nucleic acid base sequences in nucleic acid base sequence group C (C1 and C2).

[0119] Nucleic acid base sequence group A1: SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 99, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 03, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 2 34, 235, 236, 238, 239, 240, 241, 242, 247, 248, 253, 254, 255, 256, 258, 259, 263, 264, 274, 276, 277, 278, 280, 281, 283, 286, 287, 288, 291, 292, 293, 294 4, 296, 297, 298, 299, 300, 302, 303, 304, 305, 306, 307, 309, 310, 311, 313, 314, 315, 316, 317, 319, 320, 321, 323, 324, 325, 326, 327, 328, 329, 330, 331 , 332, 333, 335, 337, 338, 339, 340, 341, 342, 344, 345, 346, 347, 348, 349, 350, 355, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 369, 371, 372,373, 374, 375, 376, 377, 378, 379, 380, 382, ​​392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436 , 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486 and 487.

[0120] Nucleic acid base sequence group A2: The group consisting of SEQ ID NOs: 488, 489, 490, 491, 492, 494, 513, 515, 533, 534, 544, 551, 552, 554, 566, 574, 582, 585, 586, 589, 592, 593, 595, 596, 638, 639, 642, 644, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 696, 697, 699, 706, 713, 715 and 716.

[0121] Nucleic acid sequence group A3: The group consisting of SEQ ID NOs: 722, 723, 724, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 748, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769 and 770.

[0122] Nucleic acid sequence group B1: SEQ ID NOs: 19, 37, 38, 47, 55, 59, 61, 62, 67, 68, 70, 72, 75, 78, 82, 83, 84, 85, 86, 88, 89, 91, 101, 102, 103, 104, 105, 106, 107, 109, 111, 112, 113, 114, 117, 120, 121, 122, 124, 128, 138, 151, 152, 153, 154, 156, 157, 159, 160, 161, 163, 168, 169, 171, 174, 180, 181, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 228, 230, 231, 232, 233, 234, 235, 236, 2 87, 188, 189, 190, 192, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, 241, 298, 299, 302, 310, 316, 320, 326, 327, 328, 332, 333, 337, 345, 346, 350, 355, 357, 358, 361, 362, 363, 364, 365, 366, 367, 372, 375, 376, 377, 378, 379, 382, ​​394, 395, 397, 398, 400, 401, 403, 404, 407, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429 , 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 477, 478, 479, 480, 482, 483, 484, 485, and 486.

[0123] Nucleic acid sequence group B2: The group consisting of SEQ ID NOs: 488, 489, 490, 491, 492, 513, 515, 533, 534, 585, 586, 589, 592, 593, 595, 596, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 697, 699, 706, 713, 715 and 716.

[0124] Nucleic acid sequence group B3: The group consisting of SEQ ID NOs: 722, 723, 724, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 748, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769 and 770.

[0125] Nucleic acid base sequence group C1: SEQ ID NOs: 128, 203, 204, 205, 206, 207, 208, 209, 215, 216, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, 363, 364, 365, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, The group consisting of 25, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, and 467.

[0126] Nucleic acid sequence group C2: The group consisting of SEQ ID NOs: 488, 489, 490, 491, 492, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 715 and 716.

[0127] In another aspect, the nucleic acid base sequence of the ASO of the present invention preferably comprises at least 8, more preferably 8, 9, 10, 11, 12, 13, 14, or 15 consecutive nucleic acid bases of any one of nucleic acid base sequences in nucleic acid base sequence groups D1, D2, and D4, and even more preferably comprises any one of nucleic acid base sequences in nucleic acid base sequence groups D1, D2, and D4. In such an aspect, the ASO of the present invention is composed of preferably 8 to 80, more preferably 12 to 80, even more preferably 12 to 50, even more preferably 16 to 20, even more preferably 16 to 18, and particularly preferably 16 nucleosides. In another aspect, the nucleic acid base sequence possessed by the ASO of the present invention preferably comprises at least 8, more preferably 8, 9, 10, 11, 12, 13, 14, or 15 consecutive nucleic acid bases of any one of the nucleic acid base sequences in nucleic acid base sequence group D3, and even more preferably comprises any one of the nucleic acid base sequences in nucleic acid base sequence group D3. In such an aspect, the ASO of the present invention is composed of preferably 8 to 80, more preferably 12 to 80, even more preferably 12 to 50, still more preferably 16 to 20, and particularly preferably 18 nucleosides.

[0128] In yet another embodiment, more preferably, the ASO has a nucleic acid base sequence containing at least 8, more preferably 8, 9, 10, 11, 12, 13, 14, or 15 consecutive nucleic acid bases of any one of the nucleic acid base sequences in nucleic acid base sequence group E, and even more preferably contains any one of the nucleic acid base sequences in nucleic acid base sequence group E. In such an embodiment, the ASO of the present invention is preferably composed of 8 to 80, more preferably 16 to 80, even more preferably 16 to 50, still more preferably 16 to 20, and particularly preferably 20 nucleosides.

[0129] Nucleic acid sequence group D1: SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156 9, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 21 8, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201 The group consisting of 1, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240 and 241. Among the SEQ ID NOs listed in the nucleic acid base sequence group D1, particularly preferred SEQ ID NOs are listed below. SEQ ID NO: 208, SEQ ID NO: 215, SEQ ID NO: 220, SEQ ID NO: 221, SEQ ID NO: 222.

[0130] Nucleic acid sequence group D2: The group consisting of sequence numbers 494, 513, 515, 533, 534, 544, 551, 552, 554, 566, 574, 582, 585, 586, 589, 592, 593, 595, 596, 638, 639, 642, 644, 661, 696, 697, 699, 706 and 713.

[0131] Nucleic acid sequence group D3: The group consisting of SEQ ID NOs: 488, 489, 490, 491, 492, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 715 and 716.

[0132] Nucleobase sequence group D4: The group consisting of SEQ ID NOs: 722, 723, 724, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 748, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769 and 770.

[0133] Nucleic acid sequence group E: SEQ ID NOs: 242, 247, 248, 253, 254, 255, 256, 258, 259, 263, 264, 274, 276, 277, 278, 280, 281, 283, 286, 287, 288, 291, 292, 293, 294, 296, 297, 298, 299, 300, 302, 303, 304, 305, 306, 307, 309, 310, 311, 313, 314, 315, 316, 317, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 23, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 335, 337, 338, 339, 340, 341, 342, 344, 345, 346, 347, 348, 349, 350, 355, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 369, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382 , 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, The group consisting of 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486 and 487.

[0134] An ASO having a nucleobase sequence containing at least 8 consecutive nucleobases of any one of the nucleobase sequence groups D1 and D2 preferably has at least one LNA and at least one 2'-O-MCE nucleoside in each wing segment, more preferably one or two LNAs and one or two 2'-O-MCE nucleosides, and even more preferably two LNAs and one 2'-O-MCE nucleoside, or one LNA and two 2'-O-MCE nucleosides. Two LNAs and two 2'-O-MCE nucleosides may also be present. Particularly preferred is two LNAs and one 2'-O-MCE nucleoside.

[0135] An ASO having a nucleic acid base sequence containing at least eight consecutive nucleic acid bases of any one of the nucleic acid base sequences in nucleic acid base sequence group E particularly preferably has at least one 2'-O-MOE nucleoside or at least one 2'-O-MCE nucleoside in each wing segment, more preferably five 2'-O-MOE nucleosides or five 2'-O-MCE nucleosides, and even more preferably five 2'-O-MOE nucleosides.

[0136] An ASO having a nucleobase sequence containing at least 8 consecutive nucleobases of any one of the nucleobase sequences in nucleobase sequence group D3 preferably has at least one LNA and at least one 2'-O-MCE nucleoside in each wing segment, more preferably one or two LNAs and one or two 2'-O-MCE nucleosides, and particularly preferably two LNAs and two 2'-O-MCE nucleosides.

[0137] An ASO having a nucleobase sequence containing at least 8 consecutive nucleobases of any one of the nucleobase sequences in nucleobase sequence group D4 preferably has at least one LNA in each wing segment, more preferably 1 to 3 LNAs, and particularly preferably 3 LNAs.

[0138] A functional molecule may be directly or indirectly bound to the ASO of the present invention. The binding between the functional molecule and the ASO may be direct or indirect via another substance, but it is preferred that the oligonucleotide and the functional molecule are bound by a covalent bond, an ionic bond, or a hydrogen bond. From the viewpoint of high stability of the bond, it is more preferred that the functional molecule is bound by a direct covalent bond or by a covalent bond via a linker (linking group).

[0139] When the functional molecule is covalently linked to the ASO molecule, the functional molecule is preferably directly or indirectly linked to the 3' or 5' end of the ASO molecule. The bond between the linker or functional molecule and the terminal nucleoside of the ASO molecule is selected depending on the functional molecule. The linker or functional molecule and the terminal nucleoside of the ASO molecule are preferably linked by a phosphodiester bond or a modified phosphodiester bond, more preferably by a phosphodiester bond. The linker or functional molecule may be directly linked to the 3'-position oxygen atom of the 3'-terminal nucleoside or the 5'-position oxygen atom of the 5'-terminal nucleoside of the ASO molecule.

[0140] The structure of the "functional molecule" (conjugate) is not particularly limited, and its binding confers a desired function to the ASO. Desired functions include labeling, purification, and delivery to a target site. Examples of molecules that confer labeling function include compounds such as fluorescent proteins and luciferase. Examples of molecules that confer purification function include compounds such as biotin, avidin, His tag peptide, GST tag peptide, and FLAG tag peptide.

[0141] Furthermore, from the viewpoint of delivering the ASO to a target site (e.g., the brain or spinal cord) with high specificity and efficiency and controlling the expression of the ATN1 gene very effectively by the ASO, it is preferable that the functional molecule be a molecule having the function of delivering the ASO to the target site. For molecules having the delivery function, see, for example, European Journal of Pharmaceutics and Biopharmaceutics, 2016, 107, pp. 321-340; Advanced Drug Delivery Reviews, 2016, 104, pp. 78-92; Expert Opinion on Drug Delivery, 2014, 11, pp. 791-822, etc. For example, functional molecules that can deliver the ASO of the present invention to the brain, spinal cord, etc. with high specificity and efficiency include lipids and sugars (e.g., glucose, sucrose, etc.). Lipids include cholesterol; fat-soluble vitamins such as vitamin E (tocopherols, tocotrienols), vitamin A, vitamin D, and vitamin K; fatty acids; intermediate metabolites such as acylcarnitine and acyl-CoA; glycolipids; glycerides; and derivatives thereof.

[0142] Sugar derivatives that interact with the asialoglycoprotein receptor may also be used as functional molecules that can deliver the ASO of the present invention to the liver with high specificity. The "asialoglycoprotein receptor" is present on the surface of liver cells and recognizes the galactose residue of asialoglycoprotein, taking up the molecule into the cell and degrading it. The "sugar derivative that interacts with the asialoglycoprotein receptor" is preferably a compound that has a structure similar to the galactose residue and is taken up into the cell through interaction with the asialoglycoprotein receptor, such as GalNAc (N-acetylgalactosamine) derivatives, galactose derivatives, and lactose derivatives.

[0143] Functional molecules that can deliver ASOs to each organ with high specificity and efficiency by interacting with various proteins on the cell surface of that organ include receptor ligands, antibodies, and their fragment peptides or proteins.

[0144] The linker that connects the functional molecule to the ASO is not particularly limited as long as it can stably link the functional molecule to the oligonucleotide, as long as it can exhibit the function of the functional molecule as an ASO molecule. Examples of the linker include a group derived from an oligonucleotide having 1 to 20 nucleosides, a group derived from a polypeptide having 1 to 20 amino acids, an alkylene having 1 to 20 carbon atoms, and an alkenylene having 2 to 20 carbon atoms. The group derived from an oligonucleotide having 1 to 20 nucleosides is a divalent group obtained by removing a hydrogen atom or the like from the 3'-end and the 5'-end of an oligonucleotide having 1 to 20 nucleosides (a nucleoside when the number of nucleosides is 1). For examples of the group derived from an oligonucleotide having 1 to 20 nucleosides, see International Publication No. 2017 / 053995. WO 2017 / 053995 describes, for example, a 3-base linker having a TCA motif and a 1- to 5-base linker without a TCA motif. The group derived from a polypeptide having 1 to 20 amino acids is a divalent group obtained by removing two groups selected from hydroxy, a hydrogen atom, and amino, from a polypeptide having 1 to 20 amino acids (an amino acid when the number of amino acids is 1).

[0145] The ASO-containing compounds of the present invention may also contain a prodrug moiety. A prodrug is a derivative of a pharmaceutical compound having a chemically or metabolically decomposable group, which is converted into a pharmacologically active pharmaceutical compound by solvolysis or in vivo decomposition under physiological conditions. Methods for selecting and preparing suitable prodrug derivatives are described, for example, in Design of Prodrugs (Elsevier, Amsterdam, 1985). For example, prodrug moieties such as acyloxy derivatives prepared by reacting the hydroxy group of ASO (or a compound containing ASO) with a suitable acyl halide, a suitable acid anhydride, or a suitable alkyloxycarbonyl halide compound include -OC(=O)C2H5, -OC(=O)(t-Bu), -OC(=O)C 15 H 31 , -OC(=O)-(m-CO2Na-Ph), -OC(=O)CH2CH2CO2Na, -OC(=O)CH(NH2)CH3, -OC(=O)CH2N(CH3)2 or -O-CH2OC(=O)CH3, etc.

[0146] Prodrugs of compounds containing ASOs of the present invention also include complexes formed by hybridization of two or more oligonucleotides. Preferred structures (prodrugs) include double-stranded oligonucleotides (e.g., WO 2013 / 089283, WO 2017 / 068791, WO 2017 / 068790, or WO 2018 / 003739) that are complementary to the ASO (or the compound containing the ASO) and contain ribonucleoside-containing oligonucleotides (e.g., RNA), peptide nucleic acid (PNA), or deoxyribonucleoside-containing oligonucleotides (e.g., DNA), as well as single-stranded oligonucleotides in which RNA complementary to the ASO is linked via a linker (e.g., WO 2017 / 131124, WO 2018 / 143475). The linker may be an oligonucleotide linker or a linker containing a non-nucleoside structure. Examples include single-stranded oligonucleotides in which ASO and complementary RNA are directly linked (WO 2019 / 022196).

[0147] The compounds of the present invention include compounds in which two identical or different ASOs are linked together. For the structure of linking two ASOs, see, for example, WO 2017 / 131124 and WO 2018 / 143475.

[0148] Compounds containing ASOs exist not only via their tautomers and geometric isomers, but also as mixtures thereof or mixtures of individual isomers. Furthermore, when an asymmetric center exists or is generated as a result of isomerization, the compounds also exist as individual optical isomers and mixtures in any ratio. Furthermore, in the case of compounds with two or more asymmetric centers, diastereomers based on the respective optical isomers also exist. The present invention also includes compounds containing all of these forms in any ratio. Optically active compounds can be obtained by methods well known for this purpose.

[0149] For example, when a compound comprising the ASO of the present invention contains a modified phosphodiester bond (e.g., a phosphorothioate bond) and the phosphorus atom is an asymmetric atom, both oligonucleotides in which the phosphorus atom is stereoregulated and oligonucleotides in which the phosphorus atom is not stereoregulated are within the scope of the present invention.

[0150] The compounds containing ASO of the present invention, their prodrugs, or pharmacologically acceptable salts thereof can exist in any crystalline form or any hydrate depending on the manufacturing conditions, and these crystalline forms, hydrates, and mixtures thereof are also included within the scope of the present invention. They may also exist as solvates containing organic solvents such as acetone, ethanol, 1-propanol, and 2-propanol, and all of these forms are included within the scope of the present invention.

[0151] The ASO-containing compounds of the present invention can be converted into pharmacologically acceptable salts or released from the resulting salts, as needed. Examples of pharmacologically acceptable salts of ASO-containing compounds include salts with alkali metals (lithium, sodium, potassium, etc.), alkaline earth metals (calcium, etc.), magnesium, ammonium, organic bases (triethylamine, trimethylamine, etc.), amino acids (glycine, lysine, glutamic acid, etc.), inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc.), or organic acids (acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.). In particular, the partial structure represented by -P(=O)(OH)- is -P(=O)(O - )-, and may form a salt with an alkali metal (lithium, sodium, potassium, etc.), an alkaline earth metal (calcium, etc.), magnesium, ammonium, etc. Also, the partial structure represented by -P(=O)(SH)-, which forms a phosphorothioate bond, may be converted to -P(=O)(S - )-, and similarly form a salt with an alkali metal, alkaline earth metal, ammonium, etc. The same applies to other modified phosphodiester bonds. The pharmacologically acceptable salt is preferably a sodium salt.

[0152] Those skilled in the art can prepare compounds containing ASO of the present invention by appropriately selecting known methods. For example, those skilled in the art can design the nucleoside sequence of the ASO based on information on the nucleoside sequence of the target RNA and synthesize it using a commercially available automated nucleic acid synthesizer (Applied Biosystems, Beckman, GeneDesign, etc.). Synthesis can also be performed by an enzymatic reaction. Examples of such enzymes include, but are not limited to, polymerase, ligase, and restriction enzymes. That is, the method for producing a compound containing ASO according to this embodiment can include a step of extending the nucleoside chain at the 3' or 5' end.

[0153] Many methods for binding a functional molecule to an oligonucleotide are well known in the art, and reference can be made to, for example, European Journal of Pharmaceutics and Biopharmaceutics, 2016, 107, pp. 321-340, Advanced Drug Delivery Reviews, 2016, 104, pp. 78-92, Expert Opinion on Drug Delivery, 2014, 11, pp. 791-822, etc. For example, the functional molecule and linker can be bound by a known method, and then the linker can be converted into an amidite form using an amiditizing reagent or into an H-phosphonate form using an H-phosphonate reagent, and then bound to an oligonucleotide.

[0154] The resulting oligonucleotide can be purified by reverse phase column chromatography or the like to prepare a compound containing ASO.

[0155] The compound containing the ASO of the present invention or a pharmacologically acceptable salt thereof can effectively inhibit the expression of the ATN1 gene. Diseases that can be treated, prevented, or ameliorated by a nucleic acid drug using the compound containing the ASO of the present invention or a pharmacologically acceptable salt thereof are not particularly limited, as long as they are diseases for which the inhibitory effect on the expression of the ATN1 gene is effective, and examples thereof include dentatorubral-pallidoluysian atrophy.

[0156] The present invention can provide a composition containing the ASO-containing compound as an active ingredient, for example, for inhibiting ATN1 gene expression by antisense effect. In particular, the ASO-containing compound of the present invention can also provide a pharmaceutical composition for treating, preventing, and / or ameliorating diseases in which inhibition of ATN1 gene expression is effective, such as dentatorubral-pallidoluysian atrophy.

[0157] Pharmaceutical compositions containing the ASO-containing compounds of the present invention or pharmacologically acceptable salts thereof can be formulated by known pharmaceutical methods, and can be used enterally (e.g., orally) or parenterally in the form of, for example, injections, capsules, tablets, pills, liquids, powders, granules, fine granules, film-coated preparations, pellets, troches, sublingual preparations, chewable preparations, buccal preparations, pastes, syrups, suspensions, elixirs, emulsions, liniments, ointments, plasters, poultices, transdermal preparations, lotions, inhalants, aerosols, suppositories, etc.

[0158] In preparing these formulations, the pharmaceutical composition may be appropriately combined with a carrier that is pharmacologically or acceptable as a food or beverage, specifically, sterilized water, physiological saline, vegetable oil, solvent, base, emulsifier, suspending agent, surfactant, pH adjuster, stabilizer, flavoring agent, fragrance, excipient, vehicle, preservative, binder, diluent, isotonic agent, soothing agent, bulking agent, disintegrant, buffer, coating agent, lubricant, colorant, sweetener, thickener, flavoring agent, solubilizing agent, or other additives.

[0159] The administration route of the composition containing the ASO-containing compound of the present invention or a pharmacologically acceptable salt thereof is not particularly limited, and examples include enteral (oral, etc.) and parenteral administration. More preferred examples include intravenous administration, intraarterial administration, intraperitoneal administration, subcutaneous administration, intradermal administration, intratracheal administration, rectal administration, intramuscular administration, intrathecal administration, intraventricular administration, intranasal administration, and intravitreal administration, as well as administration by infusion. Even more preferred examples include intrathecal administration, intraventricular administration, and nasal administration, and particularly preferred example is intrathecal administration.

[0160] Preparations containing the ASO-containing compound of the present invention or a pharmacologically acceptable salt thereof and capable of intrathecal administration can be produced by known conventional methods. For example, a preparation containing the ASO-containing compound of the present invention or a pharmacologically acceptable salt thereof, plus additives such as a buffer and an isotonicity agent, is completely dissolved in water for injection and then sterilized by filtration. The preparation can be filled into a sterilized syringe to produce a prefilled syringe preparation, into a sterilized vial to produce an injectable preparation, or into a sterilized vial and lyophilized to produce a preparation for preparation at the time of use. Instead of sterilization by filtration, terminal sterilization such as autoclaving or gamma irradiation can be performed.

[0161] A variety of mammalian diseases can be treated, prevented, and / or ameliorated with compositions containing compounds comprising the ASOs of the invention or pharmacologically acceptable salts thereof. For example, diseases can be treated, prevented, and / or ameliorated in mammals, including, but not limited to, humans, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats, rabbits, chimpanzees, or other rodent species such as bovine, ovine, equine, canine, feline, and mouse. Humans are particularly preferred as mammals.

[0162] When a composition containing an ASO-containing compound of the present invention or a pharmacologically acceptable salt thereof is administered or ingested to a mammal, including a human, the dose or intake is preferably an effective amount. An effective amount refers to the amount of compound sufficient to produce the desired pharmacological effect in an individual requiring the drug. This amount varies depending on the age, weight, symptoms, and health condition of the individual whose disease is being treated, prevented, and / or ameliorated, the composition's formulation, and other factors, and is selected appropriately. The dose or intake is preferably 0.0001 mg / kg / day to 100 mg / kg / day in terms of ASO.

[0163] Preferred methods of using the ASOs of the invention include the following. A method for controlling the expression of the ATN1 gene, comprising a step of contacting cells with a compound comprising the ASO of the present invention or a pharmacologically acceptable salt thereof. A method for controlling the expression of the ATN1 gene in a mammal, comprising the step of administering to the mammal a pharmaceutical composition comprising a compound containing the ASO of the present invention or a pharmacologically acceptable salt thereof. Use of a compound comprising the ASO of the present invention or a pharmacologically acceptable salt thereof to control the expression of the ATN1 gene in a mammal. Use of a compound comprising the ASO of the present invention or a pharmacologically acceptable salt thereof for the manufacture of a drug for controlling the expression of the ATN1 gene in a mammal. [Example]

[0164] The present invention will be described in more detail below based on examples, but the embodiments of the present invention are not limited to the following examples.

[0165] In the tables (1 to 53) in the examples, "Cmpd No" means the compound number. In the chemical structure representations of the sequences in the Examples (chemical structures in Tables 1 to 10, 26 to 33, 48 and 51), unless otherwise specified, "(L)" means LNA, "(V)" means 2'-O-MCE nucleoside, "(m)" means 2'-O-MOE nucleoside, lowercase letters (except for the "m" in (m)) mean deoxyribonucleosides, "^" means phosphorothioate bond, "5(x)" means that the nucleobase of the deoxyribonucleoside is 5-methylcytosine, and the "5" in "5(m)," "5(V)," and "5(L)" means that the nucleobase of the nucleoside is 5-methylcytosine. In the notation of chemical structures in the examples (Tables 1 to 10, 26 to 33, 48 and 51), when there is no "^" between two adjacent nucleic acid bases, the internucleoside bond between the two nucleic acid bases is a phosphodiester bond. For example, in the notation "A(L)G(L)", the internucleoside bond between A and G is a phosphodiester bond, and in the notation "G(L)a", the internucleoside bond between G and a is a phosphodiester bond.

[0166] (Production Example 1) The antisense oligonucleotides (compounds represented by chemical structures corresponding to the compound numbers) listed in Tables 1 to 10 were prepared using an automated nucleic acid synthesizer nS-8II (Gene Design) or a 3900 DNA Synthesizer (Applied Biosystems). The titles of Tables 2 to 10 are the same as those in Table 1 and are therefore omitted.

[0167] [Table 1]

[0168] [Table 2]

[0169] [Table 3]

[0170] [Table 4]

[0171] [Table 5]

[0172] [Table 6]

[0173] [Table 7]

[0174] [Table 8]

[0175] [Table 9]

[0176] [Table 10]

[0177] The positions targeted by each antisense oligonucleotide shown in Tables 1 to 10 in the mRNA or pre-mRNA sequence of human ATN1, as well as the sequence numbers and nucleic acid base sequences corresponding to each antisense oligonucleotide, are shown in Tables 11 to 20. In the sequence notations in Tables 11 to 20, "SEQ1 START" means "SEQ ID NO: 1 start site" and indicates the position number of the 5'-most nucleoside targeted by the antisense oligonucleotide in the human ATN1 mRNA sequence (SEQ ID NO: 1). "SEQ1 END" means "SEQ ID NO: 1 end site" and indicates the position number of the 3'-most nucleoside targeted by the antisense oligonucleotide in the human ATN1 mRNA sequence (SEQ ID NO: 1). "SEQ2 START" means "SEQ ID NO: 2 start site" and indicates the position number of the 5'-most nucleoside targeted by the antisense oligonucleotide in the human ATN1 pre-mRNA sequence (SEQ ID NO: 2). "SEQ2 END" means "SEQ ID NO: 2 end site" and indicates the position number of the 3'-most nucleoside targeted by the antisense oligonucleotide in the human ATN1 pre-mRNA sequence (SEQ ID NO: 2). Each antisense oligonucleotide is targeted to either the human ATN1 mRNA, designated herein as SEQ ID NO: 1, and / or the human ATN1 pre-mRNA, designated herein as SEQ ID NO: 2 or SEQ ID NO: 717. A "-" (hyphen) indicates that the antisense oligonucleotide does not target that mRNA or pre-mRNA sequence with 100% complementarity. "SEQ No." indicates the sequence number, and "BASE SEQUENCE" indicates the nucleic acid base sequence of the antisense oligonucleotide. The title lines of Tables 12 to 20 are omitted because they are the same as those of Table 11.

[0178] [Table 11]

[0179] [Table 12]

[0180] [Table 13]

[0181] [Table 14]

[0182] [Table 15]

[0183] [Table 16]

[0184] [Table 17]

[0185] [Table 18]

[0186] [Table 19]

[0187] [Table 20]

[0188] [Evaluation Example 1] Antisense inhibition of human ATN1 in SH-SY5Y cells The effect of antisense oligonucleotides targeting the ATN1 nucleic acid, the causative gene for DRPLA, on ATN1 RNA transcripts was tested in vitro. SH-SY5Y cells were seeded in 96-well plates at a density of 12,000 cells / well. Approximately 24 hours later, they were transfected with 300 nM antisense oligonucleotides (prepared in Preparation 1) using Lipofectamin® RNAiMAX Transfection Reagent (Thermo Fisher Scientific). Approximately 48 hours later, RNA was isolated from the cells using an RNeasy Micro Kit (QIAGEN) and then reverse-transcribed to cDNA using a High-Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). The resulting cDNA was used to measure ATN1 gene expression levels by quantitative real-time PCR using TaqMan® Gene Expression Assays (Thermo Fisher Scientific). The results are presented in Tables 21-24 as the percent expression of ATN1 relative to untreated control cells. The title lines of Tables 22 to 24 are omitted because they are the same as those of Table 21.

[0189] [Table 21]

[0190] [Table 22]

[0191] [Table 23]

[0192] [Table 24]

[0193] [Evaluation Example 2] Dose-dependent antisense suppression of human ATN1 in SH-SY5Y cells The antisense oligonucleotides shown to suppress ATN1 expression in SH-SY5Y cells in Evaluation Example 1 were tested at various doses. SH-SY5Y cells were seeded at a density of 12,000 cells / well in a 96-well plate. After approximately 24 hours, each antisense oligonucleotide was transfected using Lipofectamin® RNAiMAX Transfection Reagent (Thermo Fisher Scientific) at concentrations of 0.003 nM, 0.03 nM, 0.3 nM, 3 nM, 30 nM, and 300 nM (ASO was added to achieve the final concentrations). After approximately 48 hours, RNA was isolated from the cells using an RNeasy Micro Kit (QIAGEN) and then reverse-transcribed to cDNA using a High-Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). ATN1 gene expression levels were measured using quantitative real-time PCR with TaqMan® Gene Expression Assays (Thermo Fisher Scientific). The results are expressed as the concentration at which RNA transcript levels are reduced by 50% compared to untreated control cells (IC 50 The values ​​were calculated as the mean values ​​and shown in Table 25.

[0194] [Table 25]

[0195] (Production Example 2) The antisense oligonucleotides (compounds represented by chemical structures corresponding to the compound numbers) listed in Tables 26 to 33 were prepared using an automated nucleic acid synthesizer nS-8II (Gene Design Co., Ltd.) The title lines of Tables 28 to 33 are the same as those in Table 27 and have been omitted.

[0196] [Table 26]

[0197] [Table 27]

[0198] [Table 28]

[0199] [Table 29]

[0200] [Table 30]

[0201] [Table 31]

[0202] [Table 32]

[0203] [Table 33]

[0204] The positions targeted by each antisense oligonucleotide in Tables 26 to 33 in the human ATN1 mRNA or pre-mRNA sequence, as well as the SEQ ID NO and nucleobase sequence corresponding to each antisense oligonucleotide, are shown in Tables 34 to 41. The notations in Tables 34 to 41 are the same as those in Tables 11 to 20. The title lines of Tables 36 to 41 are the same as those of Table 35 and have been omitted.

[0205] [Table 34]

[0206] [Table 35]

[0207] [Table 36]

[0208] [Table 37]

[0209] [Table 38]

[0210] [Table 39]

[0211] [Table 40]

[0212] [Table 41]

[0213] Table 42 shows the positions targeted by L-0498 to 0515 shown in Table 40 in the human ATN1 pre-mRNA sequence, as well as the sequence numbers and nucleic acid base sequences corresponding to each antisense oligonucleotide. "SEQ717 START" means "SEQ ID NO: 717 start site" and indicates the position number of the 5'-most nucleoside targeted by the antisense oligonucleotide in the human ATN1 pre-mRNA sequence (SEQ ID NO: 717). "SEQ717 END" means "SEQ ID NO: 717 end site" and indicates the position number of the 3'-most nucleoside targeted by the antisense oligonucleotide in the human ATN1 pre-mRNA sequence (SEQ ID NO: 717). The rest of the notation in Table 42 is the same as in Tables 11 to 20. SEQ ID NO: 2 corresponds to the positions 4451 to 18401 of the nucleic acid bases in SEQ ID NO: 717.

[0214] [Table 42]

[0215] [Evaluation Example 3] Antisense inhibition of human ATN1 in SH-SY5Y cells The effect of antisense oligonucleotides on ATN1 RNA transcripts was tested in vitro using the same assay method as in Example 1. The results are presented in Tables 43 and 44 as the percent expression of ATN1 relative to untreated control cells.

[0216] [Table 43]

[0217] [Table 44]

[0218] [Evaluation Example 4] Dose-dependent antisense suppression of human ATN1 in SH-SY5Y cells Using the same evaluation method as in Evaluation Example 2, the antisense oligonucleotides that showed suppression of ATN1 in SH-SY5Y cells in Evaluation Examples 1 and 3 were tested at various doses. The results were expressed as the concentration at which the RNA transcript level was reduced by 50% compared to untreated control cells (IC 50 The values ​​were calculated and shown in Table 45.

[0219] [Table 45]

[0220] [Evaluation Example 5] Antisense inhibition of human ATN1 in GM13716 cells [DRPLA patient-derived cells] The effect of antisense oligonucleotides targeting the ATN1 nucleic acid, the causative gene for DRPLA, on ATN1 RNA transcripts was tested in vitro. GM13716 cells were cultured at a density of 7,500 cells / well, and antisense oligonucleotides (prepared in Preparation Example 1) were added to a final concentration of 100 nM using Lipofectamin® RNAiMAX Transfection Reagent (Thermo Fisher Scientific). After approximately 48 hours, RNA was isolated from the cells using an RNeasy Micro Kit (QIAGEN) and then reverse-transcribed to cDNA using a High-Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). ATN1 RNA transcript levels were measured by quantitative real-time PCR using TaqMan® Gene Expression Assays (Thermo Fisher Scientific). The results are presented in Table 46 as the percent expression of ATN1 relative to untreated control cells.

[0221] [Table 46]

[0222] [Evaluation Example 6] Antisense inhibition of human ATN1 in GM13716 cells [DRPLA patient-derived cells] (Free-Uptake) The effect of antisense oligonucleotides targeting the ATN1 nucleic acid, the causative gene for DRPLA, on ATN1 RNA transcripts was tested in vitro. Antisense oligonucleotides (prepared in Preparation Example 1) were added to GM13716 cells cultured at a density of 7,500 cells / well to a final concentration of 100 nM (free uptake). After approximately 48 hours, RNA was isolated from the cells using an RNeasy Micro Kit (QIAGEN) and then reverse-transcribed to cDNA using a High-Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). ATN1 RNA transcript levels were measured by quantitative real-time PCR using TaqMan® Gene Expression Assays (Thermo Fisher Scientific). The results are presented in Table 47 as the percent expression of ATN1 compared to untreated control cells.

[0223] [Table 47]

[0224] (Production Example 3) The antisense oligonucleotides (compounds represented by chemical structures corresponding to the compound numbers) listed in Table 48 were prepared using an automated nucleic acid synthesizer nS-8II (Gene Design).

[0225] [Table 48]

[0226] The positions targeted by each antisense oligonucleotide in Table 48 in the human ATN1 mRNA or pre-mRNA sequence, as well as the SEQ ID NO and nucleobase sequence corresponding to each antisense oligonucleotide, are shown in Table 49. The notations in Table 49 are the same as those in Tables 11 to 20.

[0227] [Table 49]

[0228] [Evaluation Example 7] Antisense inhibition of human ATN1 in SH-SY5Y cells The effects of antisense oligonucleotides on ATN1 RNA transcripts were tested in vitro using the same assay method as in Example 1. The results are presented in Table 50 as percent expression of ATN1 relative to untreated control cells.

[0229] [Table 50]

[0230] (Production Example 4) The antisense oligonucleotides (compounds represented by chemical structures corresponding to the compound numbers) listed in Table 51 were prepared using an automated nucleic acid synthesizer nS-8II (Gene Design).

[0231] [Table 51]

[0232] The positions targeted by each antisense oligonucleotide in Table 51 in the human ATN1 mRNA or pre-mRNA sequence, as well as the SEQ ID NO and nucleobase sequence corresponding to each antisense oligonucleotide, are shown in Table 52. The notation in Table 52 is the same as in Tables 11 to 20.

[0233] [Table 52]

[0234] [Evaluation Example 8] Antisense inhibition of human ATN1 in SH-SY5Y cells The effect of antisense oligonucleotides on ATN1 RNA transcripts was tested in vitro using the same assay method as in Example 1. The results are presented in Table 53 as percent expression of ATN1 relative to untreated control cells.

[0235] [Table 53]

[0236] All publications or portions thereof, patents and patent applications cited herein are hereby incorporated by reference in their entirety. [Industrial Applicability]

[0237] The antisense oligonucleotides of the present invention inhibit the expression of the ATN1 gene and are therefore useful for treating, preventing, and / or ameliorating diseases in which inhibition of the expression of the ATN1 gene is effective, particularly dentatorubral-pallidoluysian atrophy.

Claims

1. A compound comprising a modified oligonucleotide consisting of 8 to 80 nucleosides and having a nucleic acid base sequence containing at least 8 consecutive nucleic acid bases of any one of the nucleic acid base sequences of SEQ ID NOs: 3 to 716, and 718 to 770, or a pharmacologically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide having a nucleobase sequence comprising any one of the nucleobase sequences of SEQ ID NOs: 3 to 716 and 718 to 770.

3. 3. The compound according to claim 1 or 2, comprising a modified oligonucleotide having a nucleic acid base sequence of any one of SEQ ID NOs: 3 to 716 and 718 to 770, or a pharmacologically acceptable salt thereof.

4. Nucleic acid base position numbers 59 to 104, 109 to 133, 173 to 192, 207 to 272, 300 to 319, 353 to 372, 419 to 434, 458 to 509, 523 to 559, 561 to 618, 626 to 685, 766 to 785, 787 to 819, 838 to 855, 880 to 922, 924 to 943, 970 to 989, 994 to 1039, 1055 to 1074, 107 9-1098, 1157-1176, 1196-1223, 1310-1329, 1339-1399, 1423-1442, 1614-1633, 1650-1670, 1806-1833, 1844-1865, 1896-1915, 1924-1992, 2023-2042, 2058-2081, 2103-2124, 2398-2417, 2480-2520, 2526- 2562, 2568-2587, 2853-2872, 2876-2923, 2931-2950, ​​2972-3016, 3072-3099, 3109-3128, 3192-3211, 3267-3290, 3333-3379, 3419-3557, 3765-3784, 3789-3853, 3888-3926, 4022-4062, 4118-4139, 4141-41 A compound or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by SEQ ID NO: 1, 56, 4218-4236, and 4266-4281, wherein the modified oligonucleotide is at least 80% complementary to a portion of the selected nucleic acid base sequence of SEQ ID NO:

1.

5. 5. The compound according to claim 4, or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of the nucleic acid base sequence represented by nucleic acid base positions 3419 to 3557 of SEQ ID NO: 1, wherein the modified oligonucleotide is at least 80% complementary to a portion of the nucleic acid base sequence represented by nucleic acid base positions 3419 to 3557 of SEQ ID NO:

1.

6. Nucleic acid base position numbers 383 to 398, 986 to 1001, 1004 to 1019, 1378 to 1393, 1398 to 1413, 1853 to 1868, 1971 to 1986, 2189 to 2204, 2522 to 2537, 2562 to 2577, 3662 to 3677, 3987 to 4002, 4217 to 4232, 4266 to 4281, 4335 to 4350, 4360 to 4375, 4477 to 4492, 4562 to 4577, 4636 to 4651, 4687 to 4702, 4734 to 4749, 4840 to 4855, 5536 to 5563, 5568 of SEQ ID NO: 2 ~5592, 5632~5651, 5666~5715, 5906~5925, 5959~5978, 6176~6191, 6215~6266, 6963~6978, 7248~7284, 7286~7343, 7351-7410, 7491~7510, 7512~75 44, 7563-7580, 7605-7647, 7649-7668, 7695-7714, 7719-7764, 7780-7799, 7804-7823, 7882-7901, 7921-7948, 8035-8054, 8064-8124, 8148-8167, 8 339-8358, 8375-8395, 8531-8558, 8569-8590, 8621-8640, 8649-8717, 8748-8767, 8783-8806, 8828-8849, 9123-9142, 9205-9245, 9336-9351, 9534 ~9570, 9576~9595, 9923~9938, 10001~10016, 10056~10071, 10274~10293, 10297~10344, 10352~10371, 10393~10437, 10493~10520, 10530~10549, 1 1. A compound comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of a nucleobase sequence selected from the group consisting of nucleobase sequences represented by: 0613 to 10632, 10688 to 10711, 10754 to 10800, 10840 to 10865, 12508 to 12680, 12723 to 12738, 13454 to 13518, 13553 to 13591, 13687 to 13727, 13783 to 13804, 13806 to 13821, 13883 to 13901, and 13931 to 13946, wherein the modified oligonucleotide isA compound or a pharmacologically acceptable salt thereof that is at least 80% complementary to a portion of the selected nucleic acid base sequence of SEQ ID NO:

2.

7. Nucleic acid base position numbers 5536 to 5563, 5568 to 5592, 5632 to 5651, 5666 to 5715, 5906 to 5925, 5959 to 5978, 6176 to 6191, 6215 to 6266, 7248 to 7284, 7286 to 7343, 7351 to 7410, 7491 to 7510, 7512 to 7544, 7563 to 7580, 7605 to 7647, 7649 to 7668, 7695 to 7714, 7719 to 777 64, 7780-7799, 7804-7823, 7882-7901, 7921-7948, 8035-8054, 8064-8124, 8148-8167, 8339-8358, 8375-8395, 8531-8558, 8569-8590, 8621-8640, 8649-8717, 8748-8767, 8783-8806, 8828-8849, 9123-9142, 9205-9245, 9534-9570 , 9576-9595, 10274-10293, 10297-10344, 10352-10371, 10393-10437, 10493-10520, 10530-10549, 10613-10632, 10688-10711, 10754-10800, 10840-10865, 12572-12680, 13454-13518, 13553-13591, 13687-13727, 13783-13804, 1 7. The compound of claim 6, or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of a nucleobase sequence selected from the group consisting of nucleobase sequences represented by SEQ ID NO: 3806-13821, 13883-13901, and 13931-13946, wherein the modified oligonucleotide is at least 80% complementary to a portion of the selected nucleobase sequence of SEQ ID NO:

2.

8. A compound comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base positions 4320 to 4390 and 12508 to 12680 of SEQ ID NO: 2, wherein the modified oligonucleotide is at least 80% complementary to a portion of the selected nucleic acid base sequence of SEQ ID NO: 2, or a pharmacologically acceptable salt thereof.

9. 8. The compound or pharmacologically acceptable salt thereof according to claim 6 or 7, comprising a modified oligonucleotide consisting of 8 to 80 nucleosides complementary to a portion of a nucleic acid base sequence selected from the group consisting of nucleic acid base sequences represented by nucleic acid base position numbers 10840 to 10865 and 12572 to 12680 of SEQ ID NO: 2, wherein the modified oligonucleotide is at least 80% complementary to a portion of the selected nucleic acid base sequence of SEQ ID NO:

2.

10. SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 99, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 2 03, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 2 34, 235, 236, 238, 239, 240, 241, 242, 247, 248, 253, 254, 255, 256, 258, 259, 263, 264, 274, 276, 277, 278, 280, 281, 283, 286, 287, 288, 291, 292, 293, 29 4, 296, 297, 298, 299, 300, 302, 303, 304, 305, 306, 307, 309, 310, 311, 313, 314, 315, 316, 317, 319, 320, 321, 323, 324, 325, 326, 327, 328, 329, 330, 331 , 332, 333, 335, 337, 338, 339, 340, 341, 342, 344, 345, 346, 347, 348, 349, 350, 355, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 369, 371, 372,373, 374, 375, 376, 377, 378, 379, 380, 382, ​​392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441 1, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 494, 513, 515, 533, 534, 544, 5 51, 552, 554, 566, 574, 582, 585, 586, 589, 592, 593, 595, 596, 638, 639, 642, 644, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 696, 697, 699, 706, 713, 715, 716, 722, 723, 724, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, The compound according to any one of claims 1 to 9, or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 8 to 80 nucleosides having a nucleobase sequence containing at least 8 consecutive nucleobases of any one nucleobase sequence selected from the group consisting of 741, 742, 743, 744, 745, 746, 748, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, and 770.

11. SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 99, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121 , 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 2 03, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 2 34, 235, 236, 238, 239, 240, 241, 242, 247, 248, 253, 254, 255, 256, 258, 259, 263, 264, 274, 276, 277, 278, 280, 281, 283, 286, 287, 288, 291, 292, 293, 29 4, 296, 297, 298, 299, 300, 302, 303, 304, 305, 306, 307, 309, 310, 311, 313, 314, 315, 316, 317, 319, 320, 321, 323, 324, 325, 326, 327, 328, 329, 330, 331 , 332, 333, 335, 337, 338, 339, 340, 341, 342, 344, 345, 346, 347, 348, 349, 350, 355, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 369, 371, 372,373, 374, 375, 376, 377, 378, 379, 380, 382, ​​392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417 7, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, The compound according to any one of claims 1 to 10, or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 8 to 80 nucleosides having a nucleobase sequence comprising at least 8 consecutive nucleobases of any one nucleobase sequence selected from the group consisting of 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, and 487.

12. SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 99, 101, 102, 103, 104, 105, 106, 107, 108, 1 09, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 1 76, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, 241, 488, 489, 490, 491, 492, 494, 513, 515, 533, 534, 544, 551, 552, 554, 566, 574, 582, 585, 586, 589, 592, 593, 595, 596, 638, 639, 642, 644, 661, 662, 663, 664, 665, 666, 667, 668, 669,670, 671, 672, 673, 674, 675, 676, 677, 696, 697, 699, 706, 713, 715, 716, 722, 723, 724, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 748, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, The compound according to any one of claims 1 to 11, or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 12 to 80 nucleosides having a nucleic acid base sequence comprising any one nucleic acid base sequence selected from the group consisting of 54, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, and 770.

13. SEQ ID NOs: 3, 4, 9, 10, 12, 13, 18, 19, 20, 21, 26, 29, 34, 37, 38, 39, 40, 44, 45, 46, 47, 48, 49, 50, 52, 55, 59, 60, 61, 62, 63, 66, 67, 68, 69, 70, 72, 74, 75, 78, 79, 82, 83, 84, 85, 86, 87, 88, 89, 91, 92, 94, 95, 97, 99, 101, 102, 103, 104, 105, 106 , 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 126, 127, 128, 131, 132, 133, 137, 138, 139, 148, 151, 152, 153, 154, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 20, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, and 241. The compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof, comprising a modified oligonucleotide consisting of 12 to 80 nucleosides having a nucleic acid base sequence comprising any one nucleic acid base sequence selected from the group consisting of: 20, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 238, 239, 240, and 241.

14. SEQ ID NOs: 242, 247, 248, 253, 254, 255, 256, 258, 259, 263, 264, 274, 276, 277, 278, 280, 281, 283, 286, 287, 288, 291, 292, 293, 294, 296, 297, 298, 299, 300, 302, 303, 304, 305, 306, 307, 309, 310, 311, 313, 314, 315, 316, 317, 319, 320, 321, 323, 324, 325, 326, 327, 328, 329 9, 330, 331, 332, 333, 335, 337, 338, 339, 340, 341, 342, 344, 345, 346, 347, 348, 349, 350, 355, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 369, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 382, ​​392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 4 04, 405, 406, 407, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, and 487, or a pharmacologically acceptable salt thereof.

15. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 14, wherein the modified oligonucleotide comprises a phosphorothioate bond.

16. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 15, wherein the modified oligonucleotide comprises at least one nucleoside selected from the group consisting of a 2'-modified nucleoside and a 2'-4'-bridged nucleoside.

17. The compound or pharmacologically acceptable salt thereof according to claim 16, wherein the 2'-4'-bridged nucleoside is at least one selected from the group consisting of LNA, ENA, cEt, AmNA, scpBNA and GuNA.

18. The compound or a pharmacologically acceptable salt thereof according to claim 17, wherein the 2'-4'-bridged nucleoside is LNA.

19. The compound or pharmacologically acceptable salt thereof according to any one of claims 16 to 18, wherein the 2'-modified nucleoside is at least one selected from the group consisting of a 2'-O-MCE nucleoside, a 2'-O-MOE nucleoside, a 2'-O-NMA nucleoside, and a 2'-O-Me nucleoside.

20. 20. The compound or pharmacologically acceptable salt thereof according to claim 19, wherein the 2'-modified nucleoside is at least one selected from the group consisting of a 2'-O-MCE nucleoside and a 2'-O-MOE nucleoside.

21. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 20, wherein the modified oligonucleotide contains 5-methylcytosine.

22. the modified oligonucleotide comprises a gap segment, a 5' wing segment, and a 3' wing segment; the gap segment comprises at least two deoxyribonucleosides, and the 5' and 3' ends of the gap segment are deoxyribonucleosides; the 3'-terminal nucleoside of the 5' wing segment is a sugar-modified nucleoside and is linked to the 5'-terminal of the gap segment; The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 21, wherein the 5'-terminal nucleoside of the 3' wing segment is a sugar-modified nucleoside and is linked to the 3'-terminal of the gap segment.

23. the gap segment consists of 5 to 30 deoxyribonucleosides, the 5' wing segment and the 3' wing segment each independently consist of 1 to 10 sugar-modified nucleosides independently selected from the group consisting of LNA, 2'-O-MCE nucleosides, and 2'-O-MOE nucleosides; each wing segment comprises at least one phosphorothioate linkage; 23. The compound of claim 22, or a pharmacologically acceptable salt thereof, wherein each cytosine in the gap segment and each wing segment is replaced with a 5-methylcytosine.

24. the gap segment consists of 8 to 12 deoxyribonucleosides, 24. The compound of claim 23, or a pharmacologically acceptable salt thereof, wherein the 5' wing segment and the 3' wing segment each independently consist of 2 to 5 sugar-modified nucleosides independently selected from the group consisting of LNA and 2'-O-MCE nucleosides, and contain at least one 2'-O-MCE nucleoside; and the gap segment comprises at least one phosphorothioate linkage.

25. the gap segment consists of 8 to 12 deoxyribonucleosides, the 5' wing segment and the 3' wing segment each independently consist of 3 to 6 sugar-modified nucleosides selected from the group consisting of 2'-O-MOE nucleosides and 2'-O-MCE nucleosides; 24. The compound of claim 23, or a pharmacologically acceptable salt thereof, wherein the gap segment comprises at least one phosphorothioate bond.

26. 26. The compound of claim 25, or a pharmacologically acceptable salt thereof, wherein the 5' wing segment and the 3' wing segment each independently consist of five 2'-O-MOE nucleosides.

27. 26. The compound or pharmacologically acceptable salt thereof according to claim 25, wherein the 5' wing segment and the 3' wing segment each independently consist of five 2'-O-MCE nucleosides.

28. 25. The compound of claim 24, or a pharmacologically acceptable salt thereof, wherein the 5' wing segment and the 3' wing segment are each independently selected from the group consisting of VLL, LVL, LLV, LVV, VLV, VVL, LLL, VVLL, VLVL, VLLV, LVLV, LLVV, LVVL, VLLL, LVLL, LLVL, LLLV, LVVV, VLVV, VVLV, and VVVL, wherein L represents an LNA and V represents a 2'-O-MCE nucleoside.

29. 25. The compound of claim 24, or a pharmacologically acceptable salt thereof, wherein the 5' wing segment and the 3' wing segment are each independently selected from the group consisting of VLL, LVL, LLV, LVV, VLV, VVL, VVLL, VLVL, LVLV, LLVV, VLLL, LVLL, LLVL, LLLV, LVVV, VLVV, VVLV, and VVVL, wherein L represents an LNA and V represents a 2'-O-MCE nucleoside.

30. The compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 29, wherein the modified oligonucleotide consists of 15 to 25 nucleosides.

31. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 30, wherein the modified oligonucleotide is an antisense oligonucleotide.

32. The compound or a pharmacologically acceptable salt thereof according to any one of claims 1 to 31, wherein the compound comprising the modified oligonucleotide comprises a prodrug moiety.

33. The compound comprising the modified oligonucleotide according to any one of claims 1 to 32, or a pharmacologically acceptable salt thereof, comprising a functional molecule.

34. The compound according to any one of claims 1 to 33, or a pharmacologically acceptable salt thereof, consisting of the modified oligonucleotide.

35. The salt according to any one of claims 1 to 34, wherein the pharmacologically acceptable salt is a sodium salt.

36. A pharmaceutical comprising the compound or pharmacologically acceptable salt according to any one of claims 1 to 35 as an active ingredient.

37. A therapeutic, preventive and / or ameliorating agent for a disease or condition for which inhibition of ATN1 gene expression is effective, comprising the compound or pharmacologically acceptable salt according to any one of claims 1 to 35 as an active ingredient.

38. An inhibitor of ATN1 gene expression, comprising the compound or pharmacologically acceptable salt according to any one of claims 1 to 35 as an active ingredient.

39. A therapeutic, preventive, and / or ameliorating agent for dentatorubral-pallidoluysian atrophy, comprising the compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 35 as an active ingredient.

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