Compounds and methods for modulating apolipoprotein c-iii expression for improving a diabetic profile

Abstract

Provided herein are improved compounds, compositions and associated methods for reducing expression of ApoCIII mRNA and protein in a subject having, or at risk of having, diabetes. Also provided herein are compounds, compositions and associated methods improving peripheral insulin sensitivity, a lipid profile and a diabetes profile as well as reducing free fatty acids and intramyocellular triglyceride deposition.

1 . A method of improving insulin sensitivity comprising, administering a compound comprising an antisense oligonucleotide 12-30 nucleobases in length targeting ApoCIII thereby improving insulin sensitivity. 
     
     
         2 .- 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein upon administration of the compound the subject exhibits improved glucose disposal rate, glucose metabolism rate, ratio of glucose metabolism to insulin, or suppression of hepatic glucose. 
     
     
         6 . The method of  claim 1 , wherein the subject has moderately controlled diabetes or uncontrolled diabetes. 
     
     
         7 . The method of  claim 1 , wherein the subject has fasting triglyceride levels ≥200 and ≤500 mg/dl. 
     
     
         8 . The method of  claim 1 , wherein ApoCIII has a nucleic acid sequence as shown in SEQ ID NO: 1 or SEQ ID NO: 2. 
     
     
         9 . The method of  claim 8 , wherein the antisense oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence of SEQ ID NO: 4. 
     
     
         10 . The method of  claim 8 , wherein the antisense oligonucleotide consists of a nucleobase sequence of SEQ ID NO: 4. 
     
     
         11 . The method of  claim 8 , wherein the nucleobase sequence of the antisense oligonucleotide is at least 80%, at least 90% or 100% complementary to a nucleobase sequence of SEQ ID NO: 1 or SEQ ID NO: 2. 
     
     
         12 . The method of  claim 1 , wherein the antisense oligonucleotide consists of a single-stranded modified oligonucleotide. 
     
     
         13 . The method of  claim 1 , wherein the antisense oligonucleotide consists of 20 linked nucleosides. 
     
     
         14 . The method of  claim 1 , wherein the antisense oligonucleotide has at least one modified internucleoside linkage, sugar moiety or nucleobase. 
     
     
         15 . The method of  claim 14 , wherein the internucleoside linkage of the antisense oligonucleotide is a phosphorothioate internucleoside linkage, the modified sugar is a bicyclic sugar or 2′-O-methyoxyethyl and the modified nucleobase is a 5-methylcytosine. 
     
     
         16 . The method of  claim 1 , wherein the antisense 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 linked nucleosides;   
       wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
     
     
         17 . The method of  claim 1 , wherein the antisense oligonucleotide comprises:
 (a) a gap segment consisting of 10 linked deoxynucleosides;   (b) a 5′ wing segment consisting of 5 linked nucleosides;   (c) a 3′ wing segment consisting 5 linked nucleosides;   
       wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methyoxyethyl sugar, wherein each cytosine is a 5′-methylcytosine, and wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
         18 . A method of improving insulin sensitivity in a subject comprising, selecting a subject with moderately controlled diabetes or uncontrolled diabetes and administering to the subject a therapeutically effective amount of a compound comprising a antisense oligonucleotide having the sequence of SEQ ID NO: 4 wherein the antisense oligonucleotide comprises:
 (a) a gap segment consisting of 10 linked deoxynucleosides;   (b) a 5′ wing segment consisting of 5 linked nucleosides;   (c) a 3′ wing segment consisting 5 linked nucleosides;   
       wherein the gap segment is positioned immediately adjacent to and between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methyoxyethyl sugar, wherein each cytosine is a 5′-methylcytosine, wherein each internucleoside linkage is a phosphorothioate linkage, and wherein the insulin sensitivity is improved. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the compound is parenterally administered. 
     
     
         21 . The method of  claim 20 , wherein the parenteral administration is subcutaneous administration. 
     
     
         22 . The method of  claim 1 , further comprising administration of a second agent. 
     
     
         23 . The method of  claim 22 , wherein the second agent is selected from an ApoCIII lowering agent, cholesterol lowering agent, non-HDL lipid lowering agent, LDL lowering agent, TG lowering agent, cholesterol lowering agent, HDL raising agent, fish oil, niacin, fibrate, statin, DCCR (salt of diazoxide), glucose-lowering agent or anti-diabetic agents. 
     
     
         24 . The method of  claim 22 , wherein the second agent is metformin. 
     
     
         25 . The method of  claim 22 , wherein the second agent is administered concomitantly or sequentially with the compound. 
     
     
         26 . The method of  claim 1 , wherein the antisense oligonucleotide is in a salt form. 
     
     
         27 . The method of  claim 1 , wherein the compound is in a composition comprising a pharmaceutically acceptable carrier or diluent. 
     
     
         28 . The method of  claim 1 , wherein the insulin sensitivity is peripheral insulin sensitivity.