IP Library › Granted Patent US 12,600,970
Granted Patent B2
US 12,600,970 · App. 18/330,084 · Granted Apr 14, 2026

Compositions for modulating C9ORF72 expression

Inventors: C. Frank Bennett (Carlsbad, CA); Susan M. Freier (San Diego, CA); Frank Rigo (Carlsbad, CA); Eric E. Swayze (Encinitas, CA)
Assignee: Ionis Pharmaceuticals, Inc.
C12N15/113C12N2310/11C12N2310/313C12N2310/315C12N2310/322C12N2310/3233C12N2310/3341C12N2310/341C12N2310/346
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Quick Facts
Patent No.
US 12,600,970
App. No.
18/330,084
Granted
Apr 14, 2026
Kind
B2
Abstract

Disclosed herein are compositions and methods for reducing expression of C9ORF72 mRNA and protein in an animal with C9ORF72 specific inhibitors. Such methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof. Such C9ORF72 specific inhibitors include antisense compounds. Examples of neurodegenerative diseases that can be treated, prevented, and ameliorated with the administration C9ORF72 specific inhibitors include amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), corticalbasal degeneration syndrome (CBD), atypical Parkinsonian syndrome, and olivopontocerellar degeneration (OPCD).

Claims (36)

1 . A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and comprising a nucleobase sequence comprising at least 8 contiguous nucleobases of SEQ ID NOs: 30-107, wherein the modified oligonucleotide comprises:

a gap segment consisting of linked deoxynucleosides;

a 5′ wing segment consisting of linked nucleosides; and

a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

2 . The compound of claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 75% complementary to an equal length portion of a human C9ORF72 nucleic acid of any one of SEQ ID NOs: 1-10.

3 . The compound of claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage.

4 . The compound of claim 3 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

5 . The compound of claim 1 , wherein modified the modified sugar comprises a bicyclic sugar moiety or a non-bicyclic 2′-modified sugar moiety.

6 . The compound of claim 5 , wherein:

(a) the bicyclic sugar comprises a chemical bridge between the 4′ and 2′ positions of the sugar, wherein the chemical bridge is selected from: 4′-CH(R)—O-2′ and 4′-(CH2)2-O-2′, wherein R is independently H, C1-C6 alkyl, and C1-C6 alkoxy; or

(b) the non-bicyclic 2′-modified sugar moiety comprises a 2′-O-methoxyethyl group or a 2′-O-methyl group.

7 . A compound comprising a single-stranded antisense oligonucleotide consisting of 12 to 30 linked nucleosides and comprising a nucleobase sequence comprising at least 8 contiguous nucleobases of SEQ ID NOs: 180-257, wherein the single-stranded antisense oligonucleotide comprises:

a gap segment consisting of linked deoxynucleosides;

a 5′ wing segment consisting of linked nucleosides; and

a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

8 . The compound of claim 7 , wherein the nucleobase sequence of the single-stranded antisense oligonucleotide is at least 75% complementary to an equal length portion of a human C9ORF72 nucleic acid of any one of SEQ ID NOs: 1-10.

9 . The compound of claim 7 , wherein the single-stranded antisense oligonucleotide comprises at least one modified internucleoside linkage.

10 . The compound of claim 9 , wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.

11 . The compound of claim 7 , wherein the modified sugar comprises a bicyclic sugar moiety or a non-bicyclic 2′-modified sugar moiety.

12 . The compound of claim 11 , wherein:

(a) the bicyclic sugar comprises a chemical bridge between the 4′ and 2′ positions of the sugar, wherein the chemical bridge is selected from: 4′-CH(R)—O-2′ and 4′-(CH2)2-O-2′, wherein R is independently H, C1-C6 alkyl, and C1-C6 alkoxy; or

(b) the non-bicyclic 2′-modified sugar moiety comprises a 2′-O-methoxyethyl group or a 2′-O-methyl group.

13 . The compound of claim 1 , wherein the modified antisense oligonucleotide consists of 12 to 50 linked nucleosides and has a nucleobase sequence comprising a nucleobase sequence having at least 10 contiguous nucleobases of any one of SEQ ID NOs: 30-107.

14 . The compound of claim 1 , wherein the modified antisense oligonucleotide consists of 12 to 50 linked nucleosides and has a nucleobase sequence comprising a nucleobase sequence having at least 12 contiguous nucleobases of any one of SEQ ID NOs: 30-107.

15 . The compound of claim 1 , wherein the modified antisense oligonucleotide consists of 14 to 50 linked nucleosides and has a nucleobase sequence comprising a nucleobase sequence having at least 14 contiguous nucleobases of any one of SEQ ID NOs: 30-107.

16 . The compound of claim 1 , wherein the modified antisense oligonucleotide consists of 16 to 50 linked nucleosides and has a nucleobase sequence comprising a nucleobase sequence having at least 16 contiguous nucleobases of any one of SEQ ID NOs: 30-107.

17 . The compound of claim 2 , wherein the nucleobase sequence of the modified antisense oligonucleotide is at least 90% complementary to an equal length portion of a human C9ORF72 nucleic acid of any one of SEQ ID NOs: 1-10.

18 . The compound of claim 2 , wherein the nucleobase sequence of the modified antisense oligonucleotide is 100% complementary to an equal length portion of a human C9ORF72 nucleic acid of any one of SEQ ID NOs: 1-10.

19 . The compound of claim 7 , wherein the modified antisense oligonucleotide consists of 12 to 50 linked nucleosides and has a nucleobase sequence comprising a nucleobase sequence having at least 10 contiguous nucleobases of any one of SEQ ID NOs: 180-257.

20 . The compound of claim 7 , wherein the modified antisense oligonucleotide consists of 12 to 50 linked nucleosides and has a nucleobase sequence comprising a nucleobase sequence having at least 12 contiguous nucleobases of any one of SEQ ID NOs: 180-257.

21 . The compound of claim 7 , wherein the modified antisense oligonucleotide consists of 14 to 50 linked nucleosides and has a nucleobase sequence comprising a nucleobase sequence having at least 14 contiguous nucleobases of any one of SEQ ID NOs: 180-257.

22 . The compound of claim 7 , wherein the modified antisense oligonucleotide consists of 16 to 50 linked nucleosides and has a nucleobase sequence comprising a nucleobase sequence having at least 16 contiguous nucleobases of any one of SEQ ID NOs: 180-257.

23 . The compound of claim 8 , wherein the nucleobase sequence of the modified antisense oligonucleotide is at least 90% complementary to an equal length portion of a human C9ORF72 nucleic acid of any one of SEQ ID NOs: 1-10.

24 . The compound of claim 8 , wherein the nucleobase sequence of the modified antisense oligonucleotide is 100% complementary to an equal length portion of a human C9ORF72 nucleic acid of any one of SEQ ID NOs: 1-10.

Continuity (4)
Continuation 16546283 · Aug 20, 2019
Continuation 14436024
Provisional Application 61714132 · Oct 15, 2012
Related Publication 20240200067A1 · Jun 20, 2024
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