Compositions for modulating c9orf72 expression

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).

1 .- 41 . (canceled) 
     
     
         42 . A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to an equal length portion of a C9ORF72 nucleic acid, and wherein the modified oligonucleotide comprises at least one modification selected from a modified sugar, a sugar surrogate, and a modified internucleoside linkage. 
     
     
         43 . The compound of  claim 42 , wherein the C9ORF72 nucleic acid is any of SEQ ID NO: 1, SEQ ID NO: 2, and/or SEQ ID NO: 3. 
     
     
         44 . A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 12 consecutive nucleobases of any of the nucleobase sequences of SEQ ID Nos: 30-369. 
     
     
         45 . A compound comprising a modified oligonucleotide consisting of 12 to 50 linked nucleosides and having a nucleobase sequence comprising at least 12 contiguous nucleobases 100% complementary to an equal length portion of nucleobases
 (i) 1,446-1,479 of SEQ ID NO: 2;   (ii) 2,209-2,238 of SEQ ID NO: 2;   (iii) 7,870-7,949 of SEQ ID NO: 2;   (iv) 7,990-8,072 of SEQ ID NO: 2;   (v) 8,080-8,129 of SEQ ID NO: 2;   (vi) 8,200-8,258 of SEQ ID NO: 2;   (vii) 13,357-13,409 of SEQ ID NO: 2;   (viii) 24,306-24,340 of SEQ ID NO: 2;   (ix) 26,630-26,649 of SEQ ID NO: 2; or   (x) 27,037-27,075 of SEQ ID NO: 2.   
     
     
         46 . The compound of  claim 45 , wherein:
 (i) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 288, 340-343, 346, 348, 349, 352, 354-356, 358-361, and 365-368;   (ii) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 206-208;   (iii) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 33-37 and 321-323;   (iv) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 40-47, 324, and 325;   (v) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 50, 51, 326, and 327;   (vi) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 56, 57, 58, 330, and 331;   (vii) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 72-76;   (viii) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 130-133;   (ix) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 140-142; or   (x) the nucleobase sequence of the modified oligonucleotide comprises at least 12 contiguous nucleobases of SEQ ID Nos: 164-166.   
     
     
         47 . The compound of  claim 42 , wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides. 
     
     
         48 . The compound of  claim 44 , wherein the nucleobase sequence of the modified oligonucleotide is:
 a) at least 90% complementary to an equal length portion of SEQ ID NO: 2; or   b) 100% complementary to an equal length portion of SEQ ID NO: 2.   
     
     
         49 . The compound of  claim 42 , wherein the modified oligonucleotide is a single-stranded modified oligonucleotide. 
     
     
         50 . The compound of  claim 49 , wherein the single-stranded modified oligonucleotide is a gapmer. 
     
     
         51 . The compound of  claim 42 , wherein:
 a) at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage, optionally wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage; or   b) each internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage, optionally wherein the modified internucleoside linkage is a phosphorothioate internucleoside linkage.   
     
     
         52 . The compound of  claim 42 , wherein at least one nucleobase of the modified oligonucleotide is a modified nucleobase, optionally wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         53 . The compound of  claim 42 , wherein:
 a) at least one nucleoside of the modified oligonucleotide comprises a modified sugar;   or   b) each nucleoside of the modified oligonucleotide comprises a modified sugar.   
     
     
         54 . The compound of  claim 53 , wherein the modified sugar is a bicyclic sugar. 
     
     
         55 . The compound of  claim 54 , wherein 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′-(CH 2 ) 2 —O-2′, wherein R is H, C 1 -C 6  alkyl, or C 1 -C 6  alkoxy, optionally wherein the chemical bridge is 4′-CH(R)—O-2′ and wherein R is:
 a) methyl; 
 b) H; or 
 c) —CH 2 —O—CH 3 . 
 
     
     
         56 . The compound of  claim 53 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl group or a 2′-O-methyl group. 
     
     
         57 . The compound of  claim 42 , wherein at least one nucleoside of the oligonucleotide comprises a sugar surrogate, optionally wherein the sugar surrogate is a morpholino or a peptide nucleic acid. 
     
     
         58 . The compound of  claim 42 , wherein the modified oligonucleotide has a nucleobase sequence complementary to a region of C9ORF72 other than a hexanucleotide repeat expansion, wherein the hexanucleotide repeat expansion comprises any of GGGGCC, GGGGGG, GGGGCG, and GGGGGC. 
     
     
         59 . The compound of  claim 42 , wherein the modified oligonucleotide is a double-stranded modified oligonucleotide. 
     
     
         60 . The compound of  claim 42 , consisting of the modified oligonucleotide. 
     
     
         61 . A conjugated antisense compound comprising the compound of  claim 42 . 
     
     
         62 . A double-stranded compound comprising the compound of  claim 42 . 
     
     
         63 . A conjugated antisense compound comprising the double-stranded compound of  claim 62 . 
     
     
         64 . A composition comprising a compound according to  claim 42  and a pharmaceutically acceptable carrier or diluent. 
     
     
         65 . The composition of  claim 64 , wherein:
 a) the pharmaceutically acceptable diluent is phosphate buffered saline (PBS); and/or   b) the oligonucleotide of the compound is a sodium salt.   
     
     
         66 . A composition comprising a conjugated antisense compound according to  claim 61  and a pharmaceutically acceptable carrier or diluent. 
     
     
         67 . The composition of  claim 66 , wherein:
 a) the pharmaceutically acceptable diluent is phosphate buffered saline (PBS); and/or   b) the oligonucleotide of the compound is a sodium salt.