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.

1 - 13 . (canceled) 
     
     
         14 . An assay for identifying a compound that inhibits angiopoietin-like 3 (ANGPTL3) comprising:
 a) contacting cells with a compound comprising a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to ANGPTL3;   b) measuring an amount of ANGPTL3 produced by the cells contacted by the compound targeting ANGPTL3; and   c) comparing the amount of ANGPTL3 produced from the cells contacted with the compound targeting ANGPTL3 to an amount of ANGPTL3 produced by cells not contacted with the compound targeting ANGPTL3;   wherein a reduction in ANGPTL3 production by the cells contacted by the compound targeting ANGPTL3 compared to the production of ANGPTL3 produced by cells not contacted by the compound targeting ANGPTL3 identifies the compound that inhibits ANGPTL3.   
     
     
         15 . A kit for decreasing angiopoietin-like 3 (ANGPTL3) wherein the kit comprises: a) a compound comprising a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to ANGPTL3, wherein the compound reduces expression of ANGPTL3 by at least 40%, and b) a label. 
     
     
         16 . The kit of  claim 14 , wherein the kit further comprises a second agent. 
     
     
         17 . A method for treating cardiovascular disease in a subject, comprising: administering a therapeutically effective amount of a compound comprising a modified oligonucleotide 10 to 30 linked nucleosides in length targeted to angiopoietin-like protein 3 (ANGPTL3) to a subject in need thereof. 
     
     
         18 . The method of  claim 17 , comprising identifying a subject in need of treatment of cardiovascular disease and administering the compound to the subject. 
     
     
         19 . The method of  claim 17 , wherein expression of ANGPTL3 is reduced by at least 40% in the subject. 
     
     
         20 . The method of  claim 17 , wherein the subject is a human subject. 
     
     
         21 . The method of  claim 17 , wherein the modified oligonucleotide is targeted to the 3′ UTR, 5′ UTR, exons, introns, exon/intron junctions, coding region, translation initiation region or translation termination region of SEQ ID NO:4. 
     
     
         22 . The method of  claim 17 , 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. 
     
     
         23 . The method of  claim 17 , wherein at least one internucleoside linkage of the modified oligonucleotide is a modified internucleoside linkage. 
     
     
         24 . The method of  claim 23 , wherein the at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         25 . The method of  claim 17 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified sugar. 
     
     
         26 . The method of  claim 25 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         27 . The method of  claim 25 , 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. 
     
     
         28 . The method of  claim 17 , wherein at least one nucleoside of the modified oligonucleotide comprises a modified nucleobase. 
     
     
         29 . The method of  claim 28 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         30 . The method of  claim 17 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         31 . The method of  claim 30 , 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. 
     
     
         32 . The method of  claim 17 , wherein the compound reduces ANGPTL3 expression in the subject and:
 a) reduces apoC-III expression levels;   b) reduces triglyceride levels;   c) reduces cholesterol levels;   d) reduces LDL levels;   e) reduces glucose levels;   f) improves insulin sensitivity; and/or   g) ameliorates a metabolic or cardiovascular disease.   
     
     
         33 . The method of  claim 17 , wherein the compound is in a salt form. 
     
     
         34 . The method of  claim 17 , wherein the compound is single-stranded. 
     
     
         35 . The method of  claim 17 , wherein the compound comprises a conjugate. 
     
     
         36 . The method of  claim 17 , wherein the compound is in a pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier. 
     
     
         37 . The method of  claim 36 , wherein the compound is in a salt form. 
     
     
         38 . The method of  claim 17 , wherein the cardiovascular disease is atherosclerosis or hepatic steatosis. 
     
     
         39 . The method of  claim 17 , wherein the cardiovascular disease is hyperlipidemia and/or dyslipidemia. 
     
     
         40 . The method of  claim 17 , wherein the administering is by parenteral administration. 
     
     
         41 . The method of  claim 40 , wherein the administering is by injection.