Antisense oligonucleotide of atn1

Patent metadata

Field	Value
Publication number	US-2023127437-A1
Application number	US-202117795867-A
Country	US
Kind code	A1
Filing date	Jan 29, 2021
Priority date	Jan 31, 2020
Publication date	Apr 27, 2023
Grant date	—

Abstract

The invention provides an antisense oligonucleotide capable of controlling ATN1 gene expression and treating dentatorubral-pallidoluysian atrophy. An inventive compound comprises a modified oligonucleotide consisting of 8 to 80 linked nucleosides and having a nucleobase sequence including at least 8 contiguous nucleobases that are complementary to a transcript of ATN1, or a pharmacologically acceptable salt thereof.

First claim

1 . A compound comprising a modified oligonucleotide which consists of 8 to 80 nucleosides and has a nucleobase sequence including at least 8 contiguous nucleobases of any one of nucleobase sequences of SEQ ID NOs: 3 to 716 and 718 to 770, or a pharmacologically acceptable salt thereof.

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

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

4 . A compound comprising a modified oligonucleotide which consists of 8 to 80 nucleosides complementary to a part in a nucleobase sequence selected from the group consisting of nucleobase sequences represented by 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, 1079 to 1098, 1157 to 1176, 1196 to 1223, 1310 to 1329, 1339 to 1399, 1423 to 1442, 1614 to 1633, 1650 to 1670, 1806 to 1833, 1844 to 1865, 1896 to 1915, 1924 to 1992, 2023 to 2042, 2058 to 2081, 2103 to 2124, 2398 to 2417, 2480 to 2520, 2526 to 2562, 2568 to 2587, 2853 to 2872, 2876 to 2923, 2931 to 2950, 2972 to 3016, 3072 to 3099, 3109 to 3128, 3192 to 3211, 3267 to 3290, 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 of nucleobases of SEQ ID NO: 1, wherein the modified oligonucleotide is at least 80% complementary to the part in the selected nucleobase sequence of SEQ ID NO: 1, or a pharmacologically acceptable salt thereof.

5 . The compound or pharmacologically acceptable salt thereof according to claim 4 , comprising a modified oligonucleotide which consists of 8 to 80 nucleosides complementary to a part in a nucleobase sequence represented by position numbers 3419 to 3557 of nucleobases of SEQ ID NO: 1, wherein the modified oligonucleotide is at least 80% complementary to the part in the nucleobase sequence represented by position numbers 3419 to 3557 of the nucleobases of SEQ ID NO: 1.

6 . A compound comprising a modified oligonucleotide which consists of 8 to 80 nucleosides complementary to a part in a nucleobase sequence selected from the group consisting of nucleobase sequences represented by 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 to 5592, 5632 to 5651, 5666 to 5715, 5906 to 5925, 5959 to 5978, 6176 to 6191, 6215 to 6266, 6963 to 6978, 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 7764, 7780 to 7799, 7804 to 7823, 7882 to 7901, 7921 to 7948, 8035 to 8054, 8064 to 8124, 8148 to 8167, 8339 to 8358, 8375 to 8395, 8531 to 8558, 8569 to 8590, 8621 to 8640, 8649 to 8717, 8748 to 8767, 8783 to 8806, 8828 to 8849, 9123 to 9142, 9205 to 9245, 9336 to 9351, 9534 to 9570, 9576 to 9595, 9923 to 9938, 10001 to 10016, 10056 to 10071, 10274 to 10293, 10297 to 10344, 10352 to 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 of nucleobases of SEQ ID NO: 2, or complementary to a part in a nucleobase sequence selected from the group consisting of nucleobase sequences represented by position numbers 4320 to 4390 and 12508 to 12680 of nucleobases of SEQ ID NO: 2, wherein the modified oligonucleotide is at least 80% complementary to the part in the selected nucleobase sequence of SEQ ID NO: 2, or a pharmacologically acceptable salt thereof.

7 . The compound or pharmacologically acceptable salt thereof according to claim 6 , comprising a modified oligonucleotide which consists of 8 to 80 nucleosides complementary to a part in a nucleobase sequence selected from the group consisting of nucleobase sequences represented by 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 7764, 7780 to 7799, 7804 to 7823, 7882 to 7901, 7921 to 7948, 8035 to 8054, 8064 to 8124, 8148 to 8167, 8339 to 8358, 8375 to 8395, 8531 to 8558, 8569 to 8590, 8621 to 8640, 8649 to 8717, 8748 to 8767, 8783 to 8806, 8828 to 8849, 9123 to 9142, 9205 to 9245, 9534 to 9570, 9576 to 9595, 10274 to 10293, 10297 to 10344, 10352 to 10371, 10393 to 10437, 10493 to 10520, 10530 to 10549, 10613 to 10632, 10688 to 10711, 10754 to 10800, 10840 to 10865, 12572 to 12680, 13454 to 13518, 13553 to 13591, 13687 to 13727, 13783 to 13804, 13806 to 13821, 13883 to 13901, and 13931 to 13946 of nucleobases of SEQ ID NO: 2, wherein the modified oligonucleotide is at least 80% complementary to the part in the selected nucleobase sequence of SEQ ID NO: 2.

8 . The compound or pharmacologically acceptable salt thereof according to claim 6 , comprising a modified oligonucleotide which consists of 8 to 80 nucleosides complementary to a part in a nucleobase sequence selected from the group consisting of nucleobase sequences represented by position numbers 4320 to 4390 and 12508 to 12680 of nucleobases of SEQ ID NO: 2, wherein the modified oligonucleotide is at least 80% complementary to the part in the selected nucleobase sequence of SEQ ID NO: 2.

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

10 . The compound or pharmacologically acceptable salt thereof according to claim 1 , comprising a modified oligonucleotide which consists of 8 to 80 nucleosides and has a nucleobase sequence including at least 8 contiguous nucleobases of any one of nucleobase sequences selected from the group consisting of 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, 238, 239, 240, 241, 242, 247, 248, 253, 254, 255, 256, 258, 259, 263, 264, 274, 276, 277, 278, 280, 281, 283, 286, 287, 28

Assignees

• Sanwa Kagaku Kenkyusho Co
• Nissan Chemical Corp

Inventors

• Hashimoto Shinji
• Goto Izumi
• Iriyama Yusuke

Classifications

• C12N2310/11

  Antisense · CPC title

• C12N2310/3341

  5-Methylcytosine · CPC title

• A61K48/00

  Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy · CPC title

• C12N2310/3231

  having an additional ring, e.g. LNA, ENA · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title