Methods and compositions for modulating apolipoprotein (a) expression

Abstract

Disclosed herein are antisense compounds and methods for decreasing apo(a) to treat, prevent, ameliorate diseases, disorders or conditions related to apo(a) or Lp(a). Certain diseases, disorders or conditions related to apo(a) or Lp(a) include inflammatory, cardiovascular and/or metabolic diseases, disorders or conditions. The antisense compounds disclosed herein can be used to treat such diseases, disorders or conditions in an individual in need thereof.

1 . A compound comprising a modified oligonucleotide consisting of 14 to 30 linked nucleosides and comprising a nucleobase sequence comprising a portion of at least 14 contiguous nucleobases complementary to an equal length portion of nucleobases 3900 to 3923 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1. 
     
     
         2 . The compound of  claim 1 , wherein the modified oligonucleotide consists of 15 to 30, 18 to 24, 19 to 22, 14 to 25, 15 to 25, 16 or 20 linked nucleosides. 
     
     
         3 . The compound of  claim 1 , wherein the modified oligonucleotide comprises a nucleobase sequence comprising a portion of at least 14, at least 16, at least 18, at least 19, or at least 20 contiguous nucleobases complementary to an equal length portion of SEQ ID NO: 1 
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 85%, at least 90%, at least 95%, or 100% complementary to SEQ ID NO: 1. 
     
     
         6 . A compound comprising a modified oligonucleotide consisting of 14 to 30 linked nucleosides and having a nucleobase sequence comprising at least 14, at least 15, at least 16, least 17, least 18, least 19, or 20 contiguous nucleobases of the nucleobase sequence of SEQ ID NO: 58. 
     
     
         7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein the modified oligonucleotide is single-stranded. 
     
     
         9 . The compound of  claim 1 , wherein at least one internucleoside linkage is a modified internucleoside linkage. 
     
     
         10 . The compound of  claim 9 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         11 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar. 
     
     
         12 . The compound of  claim 11 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         13 . The compound of  claim 11 , 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. 
     
     
         14 . The compound of  claim 1 , wherein at least one nucleoside comprises a modified nucleobase. 
     
     
         15 . The compound of  claim 14 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         16 . The compound of  claim 1 , wherein the modified oligonucleotide consists of 14 to 30 linked nucleosides and 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.   
     
     
         17 . The compound of  claim 16 , wherein the modified oligonucleotide consists of 20 linked nucleosides and 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, wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         18 . The compound of  claim 16 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         19 . A compound comprising a modified oligonucleotide consisting of 20 linked nucleosides of SEQ ID NO: 58, 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, wherein each internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         20 . A composition comprising a compound of  claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         21 . A composition comprising a compound of  claim 1 , for use in therapy. 
     
     
         22 . The compound of  claim 21 , for use in treating, preventing, or slowing progression of a disease related to elevated apo(a) and/or elevated Lp(a). 
     
     
         23 . The compound of  claim 21 , wherein the disease is an inflammatory, cardiovascular or metabolic disease, disorder or condition.