Compounds and methods for modulating c90rf72

Abstract

Disclosed herein are compounds and methods for modulating C9orf72 transcript. Such compounds and methods are useful to treat, prevent, or ameliorate neurodegenerative diseases in an individual in need thereof.

1 . A compound comprising a modified single-stranded RNA and a terminal group at the 5′-end of the modified single-stranded, wherein
 the modified single-stranded consists of 13 to 30 linked nucleosides and has a nucleobase sequence comprising a complementary region having at least 7 contiguous nucleobases complementary to an equal-length portion within a target region of a target nucleic acid, wherein the target nucleic acid is a C9orf72 transcript; and wherein the terminal group comprises a phosphorus moiety. 
 
     
     
         2 . The compound of  claim 1 , wherein the target region of the C9orf72 transcript comprises a hexanucleotide repeat. 
     
     
         3 . The compound of  claim 1 , wherein the target region of the C9orf72 transcript is within a hexanucleotide repeat region. 
     
     
         4 . The compound of  claim 1 , wherein the complementary region comprises at least 10 contiguous nucleobases complementary to an equal-length portion within the target region of the C9orf72 transcript. 
     
     
         5 . The compound of  claim 1 , wherein the complementary region comprises at least 12 contiguous nucleobases complementary to an equal-length portion within the target region of the C9orf72 transcript. 
     
     
         6 . The compound of  claim 1 , wherein the complementary region comprises at least 14 contiguous nucleobases complementary to an equal-length portion within the target region of the C9orf72 transcript. 
     
     
         7 . The compound of  claim 1 , wherein the complementary region comprises at least 16 contiguous nucleobases complementary to an equal-length portion within the target region of the C9orf72 transcript. 
     
     
         8 . The compound of  claim 1 , wherein the complementary region comprises at least 18 contiguous nucleobases complementary to an equal-length portion within the target region of the C9orf72 transcript. 
     
     
         9 . The compound of  claim 1 , wherein the C9orf72 transcript is a C9orf72 sense transcript. 
     
     
         10 . The compound of  claim 1 , wherein the C9orf72 transcript is a C9orf72 antisense transcript. 
     
     
         11 . The compound of  claim 1 , wherein the 5′-terminal nucleoside and terminal group of the compound has Formula I: 
       
         
           
           
               
               
           
         
         wherein:
 T 1  is a phosphorus moiety; 
 A has a formula selected from among: 
 
       
       
         
           
           
               
               
           
         
         
           Q 1  and Q 2  are each independently selected from among: H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 2 -C 6  alkynyl, and N(R 3 )(R 4 ); 
           Q 3  is selected from among: O, S, N(R 5 ), and C(R 6 )(R 7 ); 
           each R 3 , R 4  R 5 , R 6  and R 7  is independently selected from among: H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, and C 1 -C 6  alkoxy; 
           M 3  is selected from among: O, S, NR 14 , C(R 15 )(R 16 ), C(R 15 )(R 16 )C(R 17 )(R 18 ), C(R 15 )═C(R 17 ), OC(R 15 )(R 16 ), and OC(R 15 )(Bx 2 ); 
           R 14  is selected from among: H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, and substituted C 2 -C 6  alkynyl; 
           R 15 , R 16 , R 17  and R 18  are each independently selected from among: H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, and substituted C 2 -C 6  alkynyl; 
           if Bx 2  is present, then Bx 2  is a nucleobase and Bx 1  is selected from among: H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, and substituted C 2 -C 6  alkynyl; 
           if Bx 2  is not present, then Bx 1  is a nucleobase; 
           either each of J 4 , J 5 , J 6  and J 7  is independently selected from among: H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, and substituted C 2 -C 6  alkynyl; 
           or J 4  forms a bridge with one of J 5  or J 7  wherein the bridge comprises from 1 to 3 linked biradical groups selected from O, S, NR 19 , C(R 20 )(R 21 ), C(R 20 )═C(R 21 ), C[═C(R 20 )(R 21 )] and C(═O) and the other two of J 5 , J 6  and J 7  are independently selected from among: H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, and substituted C 2 -C 6  alkynyl; 
           each R 19 , R 20  and R 21  is independently selected from among: H, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl or substituted C 2 -C 6  alkynyl; 
           one of G 1  and G 2  is selected from among: H, OH, halogen and O—[C(R 8 )(R 9 )] n —[(C═O) m —X 1 ] j —Z; and the other of G 1  and G 2  is: O-T 2 ; 
           T 2  is an internucleoside linking group linking the 5′-terminal nucleoside of Formula I to the remainder of the single-stranded; 
           each R 8  and R 9  is independently selected from among: H, halogen, C 1 -C 6  alkyl, and substituted C 1 -C 6  alkyl; 
           X 1  is O, S or N(E 1 ); 
           Z is selected from among: H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 2 -C 6  alkenyl, substituted C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 2 -C 6  alkynyl, and N(E2)(E3); 
           E 1 , E 2  and E 3  are each independently selected from among: H, C 1 -C 6  alkyl, and substituted C 1 -C 6  alkyl; 
           n is from 1 to 6; 
           m is 0 or 1; 
           j is 0 or 1; 
         
         provided that, if j is 1, then Z is other than halogen or N(E 2 )(E 3 );
 each substituted group comprises one or more optionally protected substituent groups independently selected from among: a halogen, OJ 1 , N(J 1 )(J 2 ), =NJ 1 , SJ 1 , N 3 , CN, OC(═X 2 )J 1 , OC(═X 2 )N(J 1 )(J 2 ), and C(═X 2 )N(J 1 )(J 2 ); 
 X 2  is O, S or NJ 3 ; and 
 each J 1 , J 2  and J 3  is independently selected from among: H and C 1 -C 6  alkyl. 
 
       
     
     
         12 . The compound of  claim 11 , wherein M 3  is selected from among: O, CH═CH, OCH 2 , and OC(H)(Bx 2 ). 
     
     
         13 . The compound of  claim 5 , wherein M 3  is O. 
     
     
         14 . The compound of  claim 11 , wherein each of J 4 , J 5 , J 6  and J 7  is H. 
     
     
         15 . The compound of  claim 11 , wherein J 4  forms a bridge with either J 5  or J 7 . 
     
     
         16 . The compound of  claim 11 , wherein A has the formula: 
       
         
           
           
               
               
           
         
         wherein:
 Q 1  and Q 2  are each independently selected from among: H, halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and substituted C 1 -C 6  alkoxy. 
 
       
     
     
         17 . The compound of  claim 16 , wherein each of Q 1  and Q 2  is H. 
     
     
         18 . The compound of  claim 16 , wherein Q 1  and Q 2  are each independently selected from among: H and a halogen. 
     
     
         19 . The compound of  claim 16 , wherein one of Q 1  and Q 2  is H and the other of Q 1  and Q 2  is F, CH 3  or OCH 3 . 
     
     
         20 . The compound of  claim 11 , wherein T 1  has the formula: 
       
         
           
           
               
               
           
         
         wherein:
 R a  and R c  are each independently selected from among: hydroxyl, protected hydroxyl, thiol, protected thiol, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, substituted C 1 -C 6  alkoxy, amino, protected amino or substituted amino; and 
 R b  is O or S. 
 
       
     
     
         21 . The compound of  claim 20 , wherein R b  is O and R a  and R c  are each, independently selected from among: OH, OCH 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 . 
     
     
         22 . The compound of  claim 11 , wherein one of G 1  and G 2  is selected from among: a halogen, OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 , O(CH 2 ) 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —SCH 3 , O(CH 2 ) 2 —OCF 3 , O(CH 2 ) 3 —N(R 10 )(R 11 ), O(CH 2 ) 2 —ON(R 10 )(R 11 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 10 )(R 11 ), OCH 2 C(═O)—N(R 12 )—(CH 2 ) 2 —N(R 10 )(R 11 ), and O(CH 2 ) 2 —N(R 12 )—C(═NR 13 )[N(R 10 )(R 11 )]; wherein R 10 , R 11 , R 12  and R 13  are each, independently, H or C 1 -C 6  alkyl. 
     
     
         23 . The compound of  claim 11 , wherein one of G 1  and G 2  is selected from among: a halogen, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —O(CH 2 ) 2 —N(CH 3 ) 2 , OCH 2 C(═O)—N(H)CH 3 , OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 , and OCH 2 —N(H)—C(═NH)NH 2 . 
     
     
         24 . The compound of  claim 11 , wherein one of G 1  and G 2  is selected from among: F, OCH 3 , and O(CH 2 ) 2 —OCH 3 . 
     
     
         25 . The compound of  claim 24 , wherein one of G 1  and G 2  is O(CH 2 ) 2 —OCH 3 . 
     
     
         26 . The compound of  claim 11 , wherein the 5′-terminal nucleoside and terminal group of the compound has Formula III: 
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 26 , wherein A has the formula: 
       
         
           
           
               
               
           
         
       
       wherein Q 1  and Q 2  are each independently selected from among: H, a halogen, C 1 -C 6  alkyl, substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and substituted C 1 -C 6  alkoxy. 
     
     
         28 . The compound of  claim 27 , wherein Q 1  and Q 2  are each independently selected from among: H, F, CH 3 , and OCH 3 . 
     
     
         29 . The compound of  claim 11 , wherein the 5′-terminal nucleoside and the terminal group has Formula V: 
       
         
           
           
               
               
           
         
         wherein:
 Bx is selected from among: uracil, thymine, cytosine, 5-methyl cytosine, adenine, and guanine; 
 one of G 1  and G 2  is selected from among: a halogen, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —O(CH 2 ) 2 —N(CH 3 ) 2 , OCH 2 C(═O)—N(H)CH 3 , OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2  and OCH 2 —N(H)—C(═NH)NH 2 ; 
 and the other of G 1  and G 2  is O-T 2 , wherein T 2  is a phosphorothioate internucleoside linking group linking the compound of Formula V to the remainder of the single-stranded. 
 
       
     
     
         30 . The compound of  claim 1 , wherein the modified single-stranded comprises at least two modified sugar moieties. 
     
     
         31 . The compound of  claim 30 , wherein the modified single-stranded is fully modified. 
     
     
         32 . The compound of  claim 30 , wherein each modified sugar moiety is independently selected from among: 2′-F, 2′-MOE, 2′-OMe, LNA, F-HNA, and cEt. 
     
     
         33 - 92 . (canceled)