Compositions and methods for modulating apolipoprotein c-iii expression

Abstract

Provided herein are oligomeric compounds with conjugate groups targeting apolipoprotein C-III (ApoCIII). In certain embodiments, the ApoCIII targeting oligomeric compounds are conjugated to N-Acetylgalactosamine. Also disclosed herein are conjugated oligomeric compounds targeting ApoCIII for use in decreasing ApoCIII to treat, prevent, or ameliorate diseases, disorders or conditions related to ApoCIII. Certain diseases, disorders or conditions related to ApoCIII include inflammatory, cardiovascular and/or metabolic diseases, disorders or conditions. The conjugated oligomeric compounds disclosed herein can be used to treat such diseases, disorders or conditions in an individual in need thereof.

1 - 25 . (canceled) 
     
     
         26 . A compound comprising a modified oligonucleotide and a conjugate group, wherein the modified oligonucleotide consists of 12 to 30 linked nucleosides and comprises a nucleobase sequence comprising a portion of at least 8 contiguous nucleobases complementary to an equal length portion of nucleotides 1-338 of SEQ ID NO: 11, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 11, wherein the conjugate group comprises: 
       
         
           
           
               
               
           
         
       
       wherein each Y is selected from 0, S, a substituted or unsubstituted C1-C10 alkyl, amino, substituted amino, azido, alkenyl or alkynyl. 
     
     
         27 . The compound of  claim 26 , wherein the compound comprises a sequence selected from SEQ ID NOS: 97-112. 
     
     
         28 . The compound of  claim 26 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         29 . The compound of  claim 26 , wherein the modified oligonucleotide comprises at least one modified sugar. 
     
     
         30 . The compound of  claim 29 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         31 . The compound of  claim 29 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a constrained ethyl, a 3′-fluoro-HNA or a 4′-(CH 2 )n-O-2′ bridge, wherein n is 1 or 2. 
     
     
         32 . The compound of  claim 29 , wherein at least one modified sugar is 2′-O-methoxyethyl. 
     
     
         33 . The compound of  claim 26 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         34 . The compound of  claim 33 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         35 . The compound of  claim 26 , wherein the conjugate group is linked to the modified oligonucleotide at the 5′ end of the modified oligonucleotide. 
     
     
         36 . The compound of  claim 26 , wherein each internucleoside linkage of the modified oligonucleotide is selected from a phosphodiester internucleoside linkage and a phosphorothioate internucleoside linkage. 
     
     
         37 . The compound of  claim 36 , wherein the modified oligonucleotide comprises at least 5 phosphodiester internucleoside linkages. 
     
     
         38 . The compound of  claim 26 , wherein the modified oligonucleotide is double stranded. 
     
     
         39 . The compound of  claim 26 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides;   a 3′ wing segment consisting of linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.   
     
     
         40 . The compound of  claim 39 , wherein each internucleoside linkage in the gap segment of the modified oligonucleotide is a phosphorothioate linkage. 
     
     
         41 . The compound of  claim 40 , wherein the modified oligonucleotide further comprises at least one phosphorothioate internucleoside linkage in each wing segment. 
     
     
         42 . The compound of  claim 28 , wherein the modified oligonucleotide comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides;   a 3′ wing segment consisting of five linked nucleosides;   wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar, and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         43 . A method of treating, preventing or slowing the progression of a disease related to elevated ApoCIII comprising administering to a patient in need thereof the compound of  claim 26 .