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 plasma lipids, plasma glucose and atherosclerotic plaques in an animal. Such methods, compounds, and compositions are useful to treat, prevent, delay, or ameliorate any one or more of cardiovascular disease or metabolic disease, or a symptom thereof.

What is claimed is: 
     
         1 . A method for treating an animal with metabolic or cardiovascular disease comprising
 a. identifying said animal with metabolic or cardiovascular disease,   b. administering to said animal a therapeutically effective amount of a compound comprising a modified oligonucleotide having at least 20 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence selected from any of SEQ ID NO: 34-182   
       wherein said animal with metabolic or cardiovascular disease is treated. 
     
     
         2 . The method of  claim 1 , wherein the animal is a human. 
     
     
         3 . The method of  claim 1 , wherein the modified oligonucleotide has a nucleobase sequence at least 90%, at least 95% or 100% complementary to SEQ ID NO: 4 as measured over the entirety of said modified oligonucleotide. 
     
     
         4 . The method of  claim 1 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage. 
     
     
         5 . The method of  claim 4 , wherein the at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         6 . The method of  claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar. 
     
     
         7 . The method of  claim 6 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         8 . The method of  claim 6 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl, a (4′-CH(CH 3 )—O-2′) BNA, a (4′-CH 2 —O-2′) BNA, or a 4′ (CH 2 ) n O-2′ bridge, wherein n is 1 or 2. 
     
     
         9 . The method of  claim 1 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase. 
     
     
         10 . The method of  claim 9 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         11 . The method of  claim 1 , wherein the modified oligonucleotide comprises:
 a) a gap segment consisting of linked deoxynucleosides;   b) a 5′ wing segment consisting of linked nucleosides;   c) 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. 
     
     
         12 . The method of  claim 11 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         13 . The method of  claim 1 , wherein the compound is in a salt form. 
     
     
         14 . The method of  claim 1 , wherein the compound is single-stranded. 
     
     
         15 . The method of  claim 1 , wherein the compound comprises a conjugate. 
     
     
         16 . The method of  claim 1 , wherein the compound is in a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier. 
     
     
         17 . The method of  claim 16 , wherein the compound is in a salt form. 
     
     
         18 . The method of  claim 1 , wherein the metabolic or cardiovascular disease is atherosclerosis, hepatic steatosis, obesity, diabetes, dyslipidemia, coronary heart disease, non-alcoholic fatty liver disease (NAFLD), hyperfattyacidemia and/or metabolic syndrome. 
     
     
         19 . The method of  claim 18 , wherein the hepatic steatosis is nonalcoholic steatohepatitis (NASH) and the dyslipidemia is hyperlipidemia, hypercholesterolemia and/or hypertriglyceridemia. 
     
     
         20 . The method of  claim 1 , wherein the administering is by parenteral administration. 
     
     
         21 . The method of  claim 20 , wherein the administering is by injection. 
     
     
         22 . The method of  claim 1 , wherein the metabolic or cardiovascular disease is non-alcoholic fatty liver disease (NAFLD). 
     
     
         23 . The method of  claim 1 , wherein the metabolic or cardiovascular disease is nonalcoholic steatohepatitis (NASH).