Conjugated antisense compounds and their use

Abstract

The present disclosure provides duplexes comprising a first oligomeric compound and a second oligomeric compound wherein the second oligomeric compound comprises a conjugate group. In certain embodiments, the duplex modulates the amount or activity of a target nucleic acid in extra hepatic tissues and/or extra hepatic cells. In certain embodiments, the duplex modulates the amount or activity of a target nucleic acid in hepatic tissues and/or hepatic cells.

1 - 377 . (canceled) 
     
     
         378 . A duplex comprising a first oligomeric compound and a second oligomeric compound wherein:
 the first oligomeric compound comprises a first modified oligonucleotide consisting of 10-30 linked nucleosides, having a nucleobase sequence that is at least 80% complementary to the nucleobase sequence of the second oligomeric compound and that is at least 80% complementary to an extra-hepatic nucleic acid target;   wherein neither the first oligomeric compound nor the duplex is an RNAi compound;   the second oligomeric compound comprises a conjugate group and a second modified oligonucleotide consisting of 10-30 linked nucleosides;
 wherein the conjugate group comprises a conjugate moiety and a conjugate linker, 
 wherein the conjugate moiety is cholesterol; and wherein the conjugate linker comprises at least one cleavable moiety; and 
 wherein the extra-hepatic nucleic acid target is expressed in the brain or spinal cord. 
   
     
     
         379 . The duplex of  claim 378 , wherein the first modified oligonucleotide comprises at least one modified nucleoside. 
     
     
         380 . The duplex of  claim 379 , wherein the at least one modified nucleoside of the first modified oligonucleotide comprises a bicyclic sugar moiety. 
     
     
         381 . The duplex of  claim 380 , wherein at least one bicyclic sugar moiety comprises a 2′-4′ bridge, wherein the 2′-4′ bridge is selected from —O—CH 2 —; and —O—CH(CH 3 )—. 
     
     
         382 . The duplex of  claim 379 , wherein the at least one modified nucleoside of the first modified oligonucleotide comprises a non-bicyclic sugar modification. 
     
     
         383 . The duplex of  claim 382 , wherein at least one non-bicyclic sugar modification is selected from 2′-MOE and 2′-OMe. 
     
     
         384 . The duplex of  claim 378 , wherein the first modified oligonucleotide comprises a sugar motif having:
 a 5′-region consisting of 1-5 linked 5′-nucleosides;   a central region consisting of 6-10 linked central region nucleosides; and   a 3′-region consisting of 1-5 linked 3′-region nucleosides; wherein   the nucleosides of the 5′-region, the 3′-region, and the central region are contiguous, and the central region nucleosides each comprise an unmodified DNA sugar moiety.   
     
     
         385 . The duplex of  claim 384 , wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprise a modified sugar moiety. 
     
     
         386 . The duplex of  claim 378 , wherein the second modified oligonucleotide comprises at least one modified nucleoside. 
     
     
         387 . The duplex of  claim 386 , wherein the at least one modified nucleoside of the first modified oligonucleotide comprises a non-bicyclic sugar modification. 
     
     
         388 . The duplex of  claim 387 , wherein at least one non-bicyclic sugar modification is selected from 2′-MOE and 2′-OMe. 
     
     
         389 . The duplex of  claim 378 , wherein the second modified oligonucleotide comprises a sugar motif having:
 a 5′-region consisting of 1-5 linked 5′-nucleosides;   a central region consisting of 6-10 linked central region nucleosides; and   a 3′-region consisting of 1-5 linked 3′-region nucleosides; wherein   the nucleosides of the 5′-region, the 3′-region, and the central region are contiguous, and the central region nucleosides each comprise an unmodified RNA sugar moiety.   
     
     
         390 . The duplex of  claim 389 , wherein each of the 5′-region nucleosides and each of the 3′-region nucleosides comprise a modified sugar moiety. 
     
     
         391 . The duplex of  claim 378 , wherein the first modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         392 . The duplex of  claim 391 , wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         393 . The duplex of  claim 392 , wherein each internucleoside linkage of the first modified oligonucleotide is a phosphorothioate internucleoside linkage. 
     
     
         394 . The duplex of  claim 392 , wherein each internucleoside linkage of the first modified oligonucleotide is either an unmodified phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage. 
     
     
         395 . The duplex of  claim 378 , wherein the second modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         396 . The duplex of  claim 395 , wherein the at least one modified internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         397 . The duplex of  claim 396 , wherein each internucleoside linkage of the second modified oligonucleotide is either an unmodified phosphodiester internucleoside linkage or a phosphorothioate internucleoside linkage. 
     
     
         398 . The duplex of  claim 397 , wherein 1-3 terminal internucleoside linkages of the second modified oligonucleotide are phosphorothioate internucleoside linkages, and each remaining internucleoside linkage of the second modified oligonucleotide is a phosphodiester internucleoside linkage. 
     
     
         399 . The duplex of  claim 378 , wherein the first modified oligonucleotide and the second modified oligonucleotide are the same length, and each modified oligonucleotide consists of 12-16, 14-16, 14-18, 16-18, 14-20, 16-20, 18-20, 18-22, 14, 16, 18, or 20 linked nucleosides. 
     
     
         400 . The duplex of  claim 378 , wherein the cleavable moiety is a phosphate group. 
     
     
         401 . The duplex of  claim 378 , wherein the extra-hepatic nucleic acid target is not expressed in the liver at a significant level.