US2024026353A1PendingUtilityA1
Compounds and methods for modulating scn2a
Est. expiryAug 7, 2040(~14 yrs left)· nominal 20-yr term from priority
C12N 15/113A61P 25/00C12N 2310/341C12N 2310/322C12N 2310/3231C12N 2310/315C12N 2310/11C12N 15/1138C12N 2310/3341C12N 2310/344C12N 2310/321C12N 2310/3525A61K 48/00A61K 31/7088A61K 31/712A61P 25/08
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Claims
Abstract
Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of SCN2A RNA in a cell or subject, and in certain instances reducing the amount of SCN2A protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a disease or disorder associated with a voltage-gated sodium channel protein, such as, for example, a Developmental and Epileptic Encephalopathy, an intellectual disability, or an autism spectrum disorder. Such symptoms and hallmarks include, but are not limited to seizures, hypotonia, sensory integration disorders, motor development delays and dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, sleep problems, and sudden unexpected death in epilepsy.
Claims
exact text as granted — not AI-modified1 . An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an equal length portion of an SCN2A nucleic acid, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
2 . An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 16-2531, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
3 . An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or 18 contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs: 2532-2539, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
4 . The oligomeric compound of any of claims 1 to 3 , wherein the modified oligonucleotide is at least 90% complementary to an equal length portion of SEQ ID NO: 2 and is not more than 50% complementary to an equal length portion of SEQ ID NO: 1.
5 . An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein
a) the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 199863-199905, 227493-22755, 243124-243204, 247823-247921, 254142-254177, 168911-168945, 170026-170061, 183519-183562, 188630-188668, 199912-199962, 227419-227450, or 238173-238192 of SEQ ID NO: 2, provided that the modified oligonucleotide does not comprise more than six LNA nucleosides; or b) the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 243917-244073, 170174-170200, 176724-176751, 180772-180801, 183968-184016, 202877-202906, 224198-224217, 224199-224218, or 243918-243937 of SEQ ID NO: 2, wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
6 . An oligomeric compound comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides, wherein
a) the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of a sequence selected from SEQ ID NOs: 336, 488, 2021, 2097, 2174, 2250, 2326, 2403, 2499, 2500, 2501, 2502, 2526; 181, 259, 643, 720, 796, 2504, 2505, 2506, 2507, 2508, 2509, 2510, 2511, 2512, 2513, 2514, 2521; 491, 567, 644, 721, 797, 2177, 2253, 2315, 2329, 2406, 2527; 29, 30, 107, 108, 185, 186, 263, 264, 341, 342, 419, 420, 1796, 1871, 1948, 2025, 2101, 2178, 2254, 2330, 2503, 2517, 2522; 1016, 1093, 1104, 1169, 1246, 1323, 1400, 1477, 1554, 1708, 1785, 1860, 1937, 2014, 1631, 2090, 2539; 18, 96, 485, 561, 638, 715, 791, 868, 2247, 2323, 2400; 174, 1328, 1405, 1482, 1559, 1636, 1713, 1790, 1865, 1942, 2019; 20, 98, 253, 332, 410, 1406, 1483, 1560, 1637, 1714, 1791, 1866, 1943; 21, 411, 1407, 1484, 1561, 1638, 1715; 24, 414, 871, 948, 1025, 1100; 25, 337, 415, 490, 566, 2099, 2176, 2252, 2328, 2405; and 182; provided that the modified oligonucleotide does not comprise more than six LNA nucleosides; or b) wherein the nucleobase sequence of the modified oligonucleotide comprises at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 contiguous nucleobases of a sequence selected from SEQ ID NOs: 1090, 1166, 2484, 2485, 2487, 2493, 2496, 2497, 2498, 2533, 2534, 2535, 2537; 302, 1513, 1667, 1744, 1819, 1896, 1973; 148, 226, 1364, 1441, 1518, 1595, 1672, 1749; 227, 1292, 1369, 1446, 1523, 1600, 1677, 1754, 1829; 228, 1679, 1756, 1831, 1908, 1985, 2061, 2138, 2214, 2290; 1226, 1303, 1380, 1457, 1534, 1611; 2079; 2523; and 2477 wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar moiety and a modified internucleoside linkage.
7 . The oligomeric compound of any of claims 1 - 6 , comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or 20 contiguous nucleobases of any of SEQ ID NOs: 2487, 2493, 2510, or 2514.
8 . The oligomeric compound of any of claims 1 - 6 , comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and having a nucleobase sequence comprising at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or 18 contiguous nucleobases of SEQ ID NO: 2534.
9 . The oligomeric compound of any of claims 1 - 8 , wherein the modified oligonucleotide has a nucleobase sequence that is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the nucleobase sequence of SEQ ID NO: 1 or SEQ ID NO: 2 when measured across the entire nucleobase sequence of the modified oligonucleotide.
10 . The oligomeric compound of claim 9 wherein the modified oligonucleotide is at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to
an intronic region of the nucleobase sequence of SEQ ID NO: 2;
an untranslated region of the nucleobase sequence of SEQ ID NO: 2; or
an intron/exon junction region of the nucleobase sequence of SEQ ID NO: 2.
11 . The oligomeric compound of any of claims 1 - 10 , wherein the nucleobase sequence of the modified oligonucleotide is no more than 50%, no more than 60%, no more than 70%, no more than 80%, no more than 90%, or no more than 95% complementary to an exonic region of the nucleobase sequence of SEQ ID NO: 2.
12 . The oligomeric compound of any of claims 1 - 11 , wherein the modified oligonucleotide consists of 10 to 25, 10 to 30, 10 to 50, 12 to 20, 12 to 25, 12 to 30, 12 to 50, 13 to 20, 13 to 25, 13 to 30, 13 to 50, 14 to 20, 14 to 25, 14 to 30, 14 to 50, 15 to 20, 15 to 25, 15 to 30, 15 to 50, 16 to 18, 16 to 20, 16 to 25, 16 to 30, 16 to 50, 17 to 20, 17 to 25, 17 to 30, 17 to 50, 18 to 20, 18 to 25, 18 to 30, 18 to 50, 19 to 20, 19 to 25, 19 to 30, 19 to 50, 20 to 25, 20 to 30, 20 to 50, 21 to 25, 21 to 30, 21 to 50, 22 to 25, 22 to 30, 22 to 50, 23 to 25, 23 to 30, or 23 to 50 linked nucleosides.
13 . The oligomeric compound of any of claims 1 - 11 , wherein the modified oligonucleotide consists of 17-19 or 21-30 linked nucleosides.
14 . The oligomeric compound of any of claims 1 - 13 , wherein the modified oligonucleotide consists of 16, 17, 18, 19, or 20 linked nucleosides.
15 . The oligomeric compound of claim 14 , wherein the modified oligonucleotide consists of 20 linked nucleosides.
16 . The oligomeric compound of claim 14 , wherein the modified oligonucleotide consists of 18 linked nucleosides.
17 . The oligomeric compound of any of claims 1 - 16 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a modified sugar moiety.
18 . The oligomeric compound of claim 17 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a bicyclic sugar moiety.
19 . The oligomeric compound of claim 18 , wherein the bicyclic sugar moiety comprises a 4′-2′ bridge, wherein the 4′-2′ bridge is selected from —CH 2 —O—; and —CH(CH 3 )—O—.
20 . The oligomeric compound of any of claims 17 - 19 , wherein the modified oligonucleotide does not comprise more than six bicyclic sugar moieties.
21 . The oligomeric compound of claim 17 , wherein the modified oligonucleotide does not comprise a bicyclic sugar moiety.
22 . The oligomeric compound of any of claims 17 - 20 , wherein the modified oligonucleotide does not comprise more than six LNA sugar moieties.
23 . The oligomeric compound of any of claims 17 - 21 , wherein the modified oligonucleotide does not comprise a LNA sugar moiety.
24 . The oligomeric compound of any of claims 17 - 23 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a non-bicyclic modified sugar moiety.
25 . The oligomeric compound of claim 24 , wherein the non-bicyclic modified sugar moiety is a 2′-MOE sugar moiety or a 2′-OMe sugar moiety.
26 . The oligomeric compound of any of claims 17 - 25 , wherein the modified oligonucleotide comprises at least one modified nucleoside comprising a sugar surrogate.
27 . The oligomeric compound of claim 26 , wherein the sugar surrogate is any of morpholino, modified morpholino, PNA, THP, and F-HNA.
28 . The oligomeric compound of any of claims 1 - 27 , wherein the modified oligonucleotide is a gapmer.
29 . The oligomeric compound of any of claims 1 - 28 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 1-6 linked 5′-region nucleosides; a central region consisting of 6-10 linked central region nucleosides; and a 3′-region consisting of 1-6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
30 . The oligomeric compound of any of claims 1 - 28 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 1-6 linked 5′-region nucleosides; a central region consisting of 6-10 linked central region nucleosides; and a 3′-region consisting of 1-6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a modified sugar moiety and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
31 . The oligomeric compound of claim 29 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 5 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
32 . The oligomeric compound of claim 30 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 5 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
33 . The oligomeric compound of claim 29 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 6 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 4 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
34 . The oligomeric compound of claim 30 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 6 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 4 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
35 . The oligomeric compound of claim 29 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 4 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
36 . The oligomeric compound of claim 30 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 4 linked 5′-region nucleosides; a central region consisting of 10 linked central region nucleosides; and a 3′-region consisting of 6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
37 . The oligomeric compound of claim 29 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 4 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
38 . The oligomeric compound of claim 30 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 4 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 6 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
39 . The oligomeric compound of claim 29 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 6 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 4 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
40 . The oligomeric compound of claim 30 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 6 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 4 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
41 . The oligomeric compound of claim 29 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 5 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and at least six of the central region nucleosides comprise a 2′-β-D-deoxyribosyl sugar moiety.
42 . The oligomeric compound of claim 30 , wherein the modified oligonucleotide comprises:
a 5′-region consisting of 5 linked 5′-region nucleosides; a central region consisting of 8 linked central region nucleosides; and a 3′-region consisting of 5 linked 3′-region nucleosides; wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprises a 2′-MOE modified sugar moiety, and each of the central region nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety.
43 . The oligomeric compound of claim 29 or claim 30 , wherein the 5′-region or the 3′-region comprises at least one bicyclic nucleoside.
44 . The oligomeric compound of claim 29 or claim 30 , wherein the 5′-region or the 3′-region comprises at least one nucleoside that is not a bicyclic nucleoside.
45 . The oligomeric compound of claim 29 or claim 30 , wherein the 5′-region or the 3′-region comprises at least one nucleoside that is not a LNA nucleoside.
46 . The oligomeric compound of any of claims 1 - 45 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.
47 . The oligomeric compound of claim 46 , wherein at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage.
48 . The oligomeric compound of claim 46 or claim 47 , wherein each internucleoside linkage is a modified internucleoside linkage.
49 . The oligomeric compound of claim 48 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.
50 . The oligomeric compound of any of claims 46 - 47 , wherein at least one internucleoside linkage of the modified oligonucleotide is a phosphodiester internucleoside linkage.
51 . The oligomeric compound of any of claims 1 - 46 , wherein each internucleoside linkage of the modified oligonucleotide is independently selected from a phosphodiester or a phosphorothioate internucleoside linkage.
52 . The oligomeric compound of any of claims 1 - 47 or 50 - 51 , wherein at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, or at least 18 internucleoside linkages of the modified oligonucleotide are phosphorothioate internucleoside linkages.
53 . The oligomeric compound of claim 46 , wherein the internucleoside linkage motif of the modified oligonucleotide is selected from soooossssssssssooss, sooooossssssssssoss, sooossssssssssoooss, soosssssssssoooss, soooosssssssssoss, and sooosssssssssooss,
wherein s=a phosphorothioate internucleoside linkage and o=a phosphodiester internucleoside linkage.
54 . The oligomeric compound of any of claims 1 - 53 , wherein the modified oligonucleotide comprises at least one modified nucleobase.
55 . The oligomeric compound of claim 54 , wherein the modified nucleobase is a 5-methyl cytosine.
56 . The oligomeric compound of any of claims 1 - 55 , wherein the oligomeric compound is capable of reducing the amount of SCN2A RNA in vitro by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% when administered according to a standard in vitro assay.
57 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
(SEQ ID NO: 2493)
G es m C eo A eo T eo A eo A ds T ds m C ds m C ds m C ds A ds
T ds T ds A ds T ds A eo m C eo A es A es A e ,
wherein:
A=an adenine nucleobase,
m C=a 5-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-MOE sugar moiety,
d=a 2′-β-D-deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.
58 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
(SEQ ID NO: 2514)
m C es A eo m C eo G eo A eo m C eo A ds T ds A ds T ds T ds
T ds T ds T ds m C ds T ds A eo m C es A es m C e ,
wherein:
A=an adenine nucleobase,
m C=a 5-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-MOE sugar moiety,
d=a 2′-β-D-deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.
59 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
(SEQ ID NO: 2510)
m C es m C eo A eo m C eo G eo A eo m C ds A ds T ds A ds T ds
T ds T ds T ds T ds m C ds T eo A es m C es A e ,
wherein:
A=an adenine nucleobase,
m C=a 5-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-MOE sugar moiety,
d=a 2′-β-D-deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.
60 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
(SEQ ID NO: 2487)
T es m C eo T eo G eo m C eo A eo T ds G ds T ds A ds A ds m C ds
m C ds T ds T ds T ds A eo T es A es m C e ,
wherein:
A=an adenine nucleobase,
m C=a 5-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-MOE sugar moiety,
d=a 2′-β-D-deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.
61 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation:
(SEQ ID NO: 2493)
G es m C eo A eo T eo A eo A eo T ds m C ds m C ds m C ds A ds
T ds T ds A ds T ds A ds m C eo A es A es A e ,
wherein:
A=an adenine nucleobase,
m C=a 5-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-MOE sugar moiety,
d=a 2′-β-D-deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.
62 . An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: GT
(SEQ ID NO: 2534)
m C es T eo G eo m C eo A es T ds G ds T ds A ds A ds m C ds
m C ds T ds T eo T eo A es T es A e ,
wherein:
A=an adenine nucleobase,
m C=a 5-methyl cytosine nucleobase,
G=a guanine nucleobase,
T=a thymine nucleobase,
e=a 2′-MOE sugar moiety,
d=a 2′-β-D-deoxyribosyl sugar moiety,
s=a phosphorothioate internucleoside linkage, and
o=a phosphodiester internucleoside linkage.
63 . The oligomeric compound of any of claims 1 - 62 wherein the oligomeric compound is a singled-stranded oligomeric compound.
64 . The oligomeric compound of any of claims 1 - 63 , wherein the modified oligonucleotide of the oligomeric compound is a salt, and wherein the salt is a sodium salt or a potassium salt.
65 . The oligomeric compound of any of claims 1 - 64 , consisting of the modified oligonucleotide.
66 . The oligomeric compound of any of claims 1 - 62 , wherein the modified oligonucleotide is an RNAi compound.
67 . The oligomeric compound of any of claims 1 - 66 , further comprising a conjugate group.
68 . The oligomeric compound of claim 67 , wherein the conjugate group comprises a conjugate moiety and a conjugate linker.
69 . The oligomeric compound of claim 68 , wherein the conjugate group comprises a GalNAc cluster comprising 1-3 GalNAc ligands.
70 . The oligomeric compound of claim 68 , wherein the conjugate linker consists of a single bond.
71 . The oligomeric compound of claim 68 , wherein the conjugate linker is cleavable.
72 . The oligomeric compound of claim 68 , wherein the conjugate linker comprises 1-3 linker-nucleosides.
73 . The oligomeric compound of any of claims 67 - 72 , wherein the conjugate group is attached to the modified oligonucleotide at the 5′-end of the modified oligonucleotide.
74 . The oligomeric compound of any of claims 67 - 72 , wherein the conjugate group is attached to the modified oligonucleotide at the 3′-end of the modified oligonucleotide.
75 . The oligomeric compound of any of claims 1 - 74 further comprising a terminal group.
76 . The oligomeric compound of any of claims 1 - 71 or 73 - 75 , wherein the oligomeric compound does not comprise linker-nucleosides.
77 . A modified oligonucleotide according to the following chemical structure:
or a salt thereof.
78 . The modified oligonucleotide of claim 77 , which is the sodium salt or the potassium salt.
79 . A modified oligonucleotide according to the following chemical structure:
80 . A modified oligonucleotide according to the following chemical structure:
or a salt thereof.
81 . The modified oligonucleotide of claim 80 , which is the sodium salt or the potassium salt.
82 . A modified oligonucleotide according to the following chemical structure:
83 . A modified oligonucleotide according to the following chemical structure:
or a salt thereof.
84 . The modified oligonucleotide of claim 83 , which is the sodium salt or the potassium salt.
85 . A modified oligonucleotide according to the following chemical structure:
86 . A modified oligonucleotide according to the following chemical structure:
or a salt thereof.
87 . The modified oligonucleotide of claim 86 , which is the sodium salt or the potassium salt.
88 . A modified oligonucleotide according to the following chemical structure:
89 . A modified oligonucleotide according to the following chemical structure:
or a salt thereof.
90 . The modified oligonucleotide of claim 89 , which is the sodium salt or the potassium salt.
91 . A modified oligonucleotide according to the following chemical structure:
92 . A modified oligonucleotide according to the following chemical structure:
or a salt thereof.
93 . The modified oligonucleotide of claim 92 , which is the sodium salt or the potassium salt.
94 . A modified oligonucleotide according to the following chemical structure:
95 . A chirally enriched population of oligomeric compounds of any of claim 1 - 76 or modified oligonucleotides of any of claims 77 - 94 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having a particular stereochemical configuration.
96 . The chirally enriched population of claim 95 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Sp) configuration.
97 . The chirally enriched population of claim 95 , wherein the population is enriched for modified oligonucleotides comprising at least one particular phosphorothioate internucleoside linkage having the (Rp) configuration.
98 . The chirally enriched population of claim 95 , wherein the population is enriched for modified oligonucleotides having a particular, independently selected stereochemical configuration at each phosphorothioate internucleoside linkage.
99 . The chirally enriched population of claim 98 , wherein the population is enriched for modified oligonucleotides having the (Sp) configuration at each phosphorothioate internucleoside linkage or for modified oligonucleotides having the (Rp) configuration at each phosphorothioate internucleoside linkage.
100 . The chirally enriched population of claim 98 , wherein the population is enriched for modified oligonucleotides having the (Rp) configuration at one particular phosphorothioate internucleoside linkage and the (Sp) configuration at each of the remaining phosphorothioate internucleoside linkages.
101 . The chirally enriched population of claim 98 , wherein the population is enriched for modified oligonucleotides having at least 3 contiguous phosphorothioate internucleoside linkages in the Sp, Sp, and Rp configurations, in the 5′ to 3′ direction.
102 . A population of oligomeric compounds of any of claims 1 - 76 or modified oligonucleotides of any of claims 77 - 94 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
103 . An oligomeric duplex, comprising a first oligomeric compound and a second oligomeric compound comprising a second modified oligonucleotide, wherein the first oligomeric compound is an oligomeric compound of any of claims 1 - 76 .
104 . The oligomeric duplex of claim 103 , wherein the second oligomeric compound comprises a second modified oligonucleotide consisting of 8 to 80 linked nucleosides, and wherein the nucleobase sequence of the second modified oligonucleotide comprises a complementary region of at least 8 nucleobases that is at least 90% complementary to an equal length portion of the first modified oligonucleotide.
105 . An antisense agent comprising an antisense compound, wherein the antisense compound is an oligomeric compound of any of claims 1 - 76 or a modified oligonucleotide of any of claims 77 - 94 .
106 . The antisense agent of claim 105 , wherein the antisense agent is an oligomeric duplex of claim 103 or claim 104 .
107 . The antisense agent of claim 105 or claim 106 , wherein the antisense agent is:
i. an RNase H agent capable of reducing the amount of SCN2A nucleic acid through the activation of RNase H; or
ii. an RNAi agent capable of reducing the amount of SCN2A nucleic acid through the activation of RISC/Ago2.
108 . A pharmaceutical composition comprising an oligomeric compound of any of claims 1 - 76 , a modified oligonucleotide of any of claims 77 - 94 , a population of any of claims 95 - 102 , an oligomeric duplex of claim 103 or claim 104 , or an antisense agent of any of claims 105 - 107 , and a pharmaceutically acceptable diluent or carrier.
109 . The pharmaceutical composition of claim 108 , comprising a pharmaceutically acceptable diluent and wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid (aCSF) or phosphate-buffered saline (PBS).
110 . The pharmaceutical composition of claim 109 , wherein the pharmaceutical composition consists essentially of the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, or the antisense agent, and aCSF.
111 . The pharmaceutical composition of claim 109 , wherein the pharmaceutical composition consists essentially of the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, or the antisense agent, and PBS.
112 . A pharmaceutical composition comprising a modified oligonucleotide of any of claims 77 - 94 and a pharmaceutically acceptable diluent.
113 . The pharmaceutical composition of claim 112 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid (aCSF) or phosphate-buffered saline (PBS).
114 . The pharmaceutical composition of claim 113 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and aCSF.
115 . The pharmaceutical composition of claim 113 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
116 . A method comprising administering to a subject an oligomeric compound of any of claims 1 - 76 , a modified oligonucleotide of any of claims 77 - 94 , a population of any of claims 95 - 102 , an oligomeric duplex of claim 103 or claim 104 , an antisense agent of any of claims 105 - 107 , or a pharmaceutical composition of any of claims 108 - 115 .
117 . A method of treating a disease or disorder associated with a voltage-gated sodium channel protein, comprising administering to a subject having or at risk for developing the disease or disorder associated with a voltage-gated sodium channel protein a therapeutically effective amount of an oligomeric compound of any of claims 1 - 76 , a modified oligonucleotide of any of claims 77 - 94 , a population of any of claims 95 - 102 , an oligomeric duplex of claim 103 or claim 104 , an antisense agent of any of claims 105 - 107 , or a pharmaceutical composition of any of claims 108 - 115 , thereby treating the disease or disorder associated with a voltage-gated sodium channel protein.
118 . A method of reducing the amount of SCN2A protein in the CSF of a subject having or at risk for developing a disease or disorder associated with a voltage-gated sodium channel protein a therapeutically effective amount of an oligomeric compound of any of claims 1 - 76 , a modified oligonucleotide of any of claims 77 - 94 , a population of any of claims 95 - 102 , an oligomeric duplex of claim 103 or claim 104 , an antisense agent of any of claims 105 - 107 , or a pharmaceutical composition of any of claims 108 - 115 , thereby reducing the amount of SCN2A protein in the CSF.
119 . The method of claim 117 or claim 118 , wherein the disease or disorder is a neurodevelopmental disease.
120 . The method of claim 117 or claim 118 , wherein the disease or disorder is associated with SCN1A or SCN2A.
121 . A method of treating a disease or disorder associated with SCN2A, comprising administering to an subject having or at risk for developing a disease or disorder associated with SCN2A a therapeutically effective amount of an oligomeric compound of any of claims 1 - 76 , a modified oligonucleotide of any of claims 77 - 94 , a population of any of claims 95 - 102 , an oligomeric duplex of claim 103 or claim 104 , an antisense agent of any of claims 105 - 107 , or a pharmaceutical composition of any of claims 108 - 115 , thereby treating the disease or disorder associated with SCN2A.
122 . The method of claim 121 , wherein the disease or disorder associated with SCN2A is a Developmental and Epileptic Encephalopathy, an intellectual disability, or an autism spectrum disorder.
123 . The method of claim 122 , wherein the Developmental and Epileptic Encephalopathy is any of Early Seizure Onset Epileptic Encephalopathy (EE), Late Seizure Onset Epileptic Encephalopathy, or Benign Familial Neonatal-Infantile Seizures.
124 . The method of claim 121 , wherein the disease or disorder associated with SCN2A is any of Ohtahara Syndrome, epilepsy with migrating focal seizures of infancy, West Syndrome, Lennon-Gastaut Syndrome; Dravet Syndrome; Idiopathic/Generic Generalized Epilepsies, Temporal Lobe Epilepsy, Myoclonic Astatic Epilepsy, Migrating Partial Epilepsy of Infancy, or familial hemiplegic migraines.
125 . The method of any of claims 118 - 120 , wherein the disease or disorder is associated with SCN1A.
126 . The method of claim 125 , wherein the disease or disorder associated with SCN1A is a Developmental and Epileptic Encephalopathy.
127 . The method of claim 125 or claim 126 , wherein the Developmental and Epileptic Encephalopathy is Dravet Syndrome.
128 . The method of claim 126 or claim 127 , wherein the Developmental and Epileptic Encephalopathy is any of Ohtahara Syndrome, epilepsy with migrating focal seizures of infancy, West Syndrome, Lennon-Gastaut Syndrome; Dravet Syndrome; Idiopathic/Generic Generalized Epilepsies, Temporal Lobe Epilepsy, Myoclonic Astatic Epilepsy, Migrating Partial Epilepsy of Infancy, or familial hemiplegic migraines.
129 . The method of any of claims 117 - 128 , wherein at least one symptom or hallmark of the disease or disorder is ameliorated.
130 . The method of claim 129 , wherein the symptom or hallmark is seizures.
131 . The method of any of claim 130 , wherein the seizures are any of focal, clonic, tonic, generalized tonic and clonic, convulsive, myoclonic, absence, or obtundation status.
132 . The method of claim 130 , wherein the seizures are any of focal, clonic, tonic, or generalized tonic.
133 . The method of claim 129 , wherein the symptom or hallmark is any of seizures, hypotonia, sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, or sudden unexpected death in epilepsy.
134 . The method of claim 129 , wherein the symptom or hallmark is any of motor development delays, delayed social and language milestones, repetitive actions, uncoordinated oral movements, gastrointestinal disoders, sleep problems, or seizures.
135 . The method of any of claims 130 - 134 , wherein the seizures are frequent or prolonged.
136 . The method of any of claims 116 - 135 wherein administering the modified oligonucleotide reduces seizures, sensory integration disorders, motor dysfunctions, intellectual and cognitive dysfunctions, movement and balance dysfunctions, visual dysfunctions, delayed language and speech, gastrointestinal disorders, neurodevelopmental delays, motor development delays, delayed social milestones, repetitive actions, uncoordinated oral movements, or sleep problems, hypotonia, nystagmus, optic atrophy, respiratory distress, motor delays, cognitive dysfunction, speech dysfunction, spasticity, ataxia, seizures, or choreiform movements, or delays death in the subject.
137 . The method of any of claims 116 - 136 , wherein the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, the antisense agent, or the pharmaceutical composition is administered to the central nervous system or systemically.
138 . The method of any of claims 116 - 136 , wherein the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, the antisense agent, or the pharmaceutical composition is administered to the central nervous system and systemically.
139 . The method of any of claims 116 - 131 , wherein the oligomeric compound, the modified oligonucleotide, the population, the oligomeric duplex, the antisense agent, or the pharmaceutical composition is administered by any of intrathecally, systemically, subcutaneously, or intramuscularly.
140 . The method of any of claims 116 - 139 , wherein the subject is human.
141 . A method of reducing the amount of SCN2A RNA in a cell comprising contacting the cell with an oligomeric compound of any of claims 1 - 76 , a modified oligonucleotide of any of claims 77 - 94 , a population of any of claims 95 - 102 , an oligomeric duplex of claim 103 or claim 104 , an antisense agent of any of claims 105 - 107 , or a pharmaceutical composition of any of claims 108 - 115 , thereby reducing the amount of SCN2A RNA in the cell.
142 . A method of reducing the amount of SCN2A protein in a cell comprising contacting the cell with an oligomeric compound of any of claims 1 - 76 , a modified oligonucleotide of any of claims 77 - 94 , a population of any of claims 95 - 102 , an oligomeric duplex of claim 103 or claim 104 , an antisense agent of any of claims 105 - 107 , or a pharmaceutical composition of any of claims 108 - 115 , thereby reducing the amount of SCN2A protein in the cell.
143 . The method of claim 141 or claim 142 , wherein the cell is a cortical cell, a hippocampal cell, or a spinal cord cell.
144 . The method of any of claims 141 - 143 , wherein the cell is in an animal.
145 . The method of any of claims 141 - 144 , wherein the cell is a human cell.
146 . Use of an oligomeric compound of any of claims 1 - 76 , a modified oligonucleotide of any of claims 77 - 94 , a population of any of claims 95 - 102 , an oligomeric duplex of claim 103 or claim 104 , an antisense agent of any of claims 105 - 107 , or a pharmaceutical composition of any of claims 108 - 115 for reducing SCN2A expression in a cell.
147 . The use of claim 146 , wherein the level of SCN2A RNA in the cell is reduced.
148 . The use of claim 146 or claim 147 , wherein the level of SCN2A protein in the cell is reduced.
149 . The use of any of claims 146 - 148 , wherein the cell is a corical cell, a hippocampal cell, or a spinal cord cell.Join the waitlist — get patent alerts
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