Modulation of angiopoietin-like 3 expression

Abstract

Provided herein are methods, compounds, and compositions for reducing expression of an ANGPTL3 mRNA and protein in an animal. Also provided herein are methods, compounds, and compositions for reducing lipids and/or glucose in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate any one or more of cardiovascular disease and/or metabolic disease, or a symptom thereof, 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 at least 14 contiguous nucleobases complementary to an equal length portion of nucleobases 1140 to 1159 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 to 24, 16 or 20 linked nucleosides. 
     
     
         3 .- 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 . The compound of  claim 1 , wherein the modified oligonucleotide comprises 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: 77. 
     
     
         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 at least one 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 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 at least one 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 and having a nucleobase sequence comprising at least 14 contiguous nucleobases complementary to an equal length portion of any of SEQ ID NO: 77, 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 at least one internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         20 .- 21 . (canceled) 
     
     
         22 . The compound of  claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier or diluent. 
     
     
         23 . (canceled) 
     
     
         24 . A method for treating, preventing, or slowing progression of a disease related to elevated ANGPTL3 in an animal, comprising administering to the animal a compound comprising a modified oligonucleotide consisting of 14 to 30 linked nucleosides and comprising a nucleobase sequence comprising at least 14 contiguous nucleobases complementary to an equal length portion of nucleobases 1140 to 1159 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary to SEQ ID NO: 1, wherein administration of the compound to the animal treats, prevents or slows the progression of a disease related to elevated ANGPTL3 levels in the animal. 
     
     
         25 . The method of  claim 24 , wherein the disease is a cardiovascular and/or metabolic disease, disorder or condition. 
     
     
         26 . The method of  claim 25 , wherein the cardiovascular and/or metabolic disease, disorder or condition is obesity, diabetes, atherosclerosis, dyslipidemia, lipodystrophy, coronary heart disease, non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) hyperfattyacidemia or metabolic syndrome. 
     
     
         27 . The compound of  claim 1 , further comprising a conjugate group.