Antisense compounds and uses thereof

Abstract

The present disclosure provides oligomeric compounds. Certain such oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited, to nucleic acids in a cell. In certain embodiments, hybridization results in modulation of the amount activity or expression of the target nucleic acid in a cell.

What is claimed is: 
     
         1 .- 346 . (canceled) 
     
     
         347 . An oligomeric compound having the formula:
   5′-X s —(X o ) n —(X s ) m -(d s ) q -(X o ) r —(X s ) p —(X)-3′
   wherein   each X independently comprises a modified nucleoside;   each d comprises a 2′-deoxynucleoside;   each subscript “s” comprises a phosphorothioate internucleoside linkage;   each subscript “o” comprises a phosphodiester internucleoside linkage;   n is an integer from 0 to 4;   m is an integer from 0 to 4;   q is an integer from 5 to 10;   r is an integer from 0 to 4; and   p is an integer from 0 to 5.   
     
     
         348 . The oligomeric compound of  claim 347 , wherein m is 1. 
     
     
         349 . The oligomeric compound of  claim 348 , wherein n is 1. 
     
     
         350 . The oligomeric compound of  claim 348 , wherein n is 2. 
     
     
         351 . The oligomeric compound of  claim 348 , wherein n is 3. 
     
     
         352 . The oligomeric compound of  claim 348 , wherein r is 1. 
     
     
         353 . The oligomeric compound of  claim 348 , wherein q is 5. 
     
     
         354 . The oligomeric compound of  claim 348 , wherein q is 6. 
     
     
         355 . The oligomeric compound of  claim 348 , wherein q is 7. 
     
     
         356 . The oligomeric compound of  claim 348 , wherein q is 8. 
     
     
         357 . The oligomeric compound of  claim 348 , wherein at least one modified nucleoside comprises a 2′-substituted sugar moiety comprising a 2′ substituent selected from among: halogen, optionally substituted allyl, optionally substituted amino, azido, optionally substituted SH, CN, OCN, CF 3 , OCF 3 , O, S, or N(R m )-alkyl; O, S, or N(R m )-alkenyl; O, S or N(R m )-alkynyl; optionally substituted O-alkylenyl-O-alkyl, optionally substituted alkynyl, optionally substituted alkaryl, optionally substituted aralkyl, optionally substituted O-alkaryl, optionally substituted O-aralkyl, O(CH 2 ) 2 SCH 3 , O—(CH 2 ) 2 —O—N(R m )(R n ) or O—CH 2 —C(═O)—N(R m )(R n ), where each R m  and R n  is, independently, H, an amino protecting group or substituted or unsubstituted C 1 -C 10  alkyl;
 wherein each optionally substituted group is optionally substituted with a substituent group independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO 2 ), thiol, thioalkoxy(S-alkyl), halogen, alkyl, aryl, alkenyl and alkynyl. 
 
     
     
         358 . The oligomeric compound of  claim 357 , wherein at least one modified nucleoside comprises a 2′-substituted sugar moiety comprising a 2′-substituent 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 . 
     
     
         359 . The oligomeric compound of  claim 357 , wherein at least one modified nucleoside comprises a 2′-substituted sugar moiety comprising a 2′-substituent selected from among: F, OCH 3 , O(CH 2 ) 2 —OCH 3 . 
     
     
         360 . The oligomeric compound of  claim 359 , wherein eight modified nucleosides comprises an O(CH 2 ) 2 —OCH 3  2′-substituent. 
     
     
         361 . The oligomeric compound of  claim 359 , wherein nine modified nucleosides comprises an O(CH 2 ) 2 —OCH 3  2′-substituent. 
     
     
         362 . The oligomeric compound of  claim 359 , wherein ten modified nucleosides comprises an O(CH 2 ) 2 —OCH 3  2′-substituent. 
     
     
         363 . The oligomeric compound of  claim 348 , wherein each modified nucleoside comprises a 2′-substituted sugar moiety comprises an O(CH 2 ) 2 —OCH 3  2′-substituent. 
     
     
         364 . The oligomeric compound of  claim 348 , wherein at least one modified nucleoside comprises a bicyclic sugar moiety selected from among: cEt, cMOE, LNA, α-LNA, ENA and 2′-thio LNA. 
     
     
         365 . The oligomeric compound of  claim 348 , wherein at least two modified nucleosides comprises a bicyclic sugar moiety selected from among: cEt, cMOE, LNA, α-LNA, ENA and 2′-thio LNA. 
     
     
         366 . The oligomeric compound of  claim 348 , wherein at least three modified nucleosides comprises a bicyclic sugar moiety selected from among: cEt, cMOE, LNA, α-LNA, ENA and 2′-thio LNA.