Modulation of diacylglycerol acyltransferase 1 expression

Abstract

Compounds, compositions and methods are provided for modulating the expression of diacylglycerol acyltransferase 1. The compositions comprise oligonucleotides, targeted to nucleic acid encoding diacylglycerol acyltransferase 1. Methods of using these compounds for modulation of diacylglycerol acyltransferase 1 expression and for diagnosis and treatment of disease associated with expression of diacylglycerol acyltransferase 1, such as obesity and obesity-related conditions, are provided.

1 . A compound comprising a modified oligonucleotide 8 to 80 nucleobases in length targeted to a nucleic acid molecule encoding diacylglycerol acyltransferase 1, wherein said compound specifically hybridizes with said nucleic acid molecule (SEQ ID NO: 4) encoding diacylglycerol acyltransferase 1 and inhibits the expression of diacylglycerol acyltransferase 1. 
     
     
         2 . The compound of  claim 1 , wherein the modified oligonucleotide is 12 to 50 nucleobases in length. 
     
     
         3 . The compound of  claim 2 , wherein the modified oligonucleotide is 15 to 30 nucleobases in length. 
     
     
         4 . (canceled) 
     
     
         5 . The compound of  claim 1 , wherein the modified oligonucleotide is a single-stranded oligonucleotide. 
     
     
         6 . The compound of  claim 1 , wherein the modified oligonucleotide is a DNA oligonucleotide. 
     
     
         7 . The compound of  claim 1 , wherein the modified oligonucleotide is an RNA oligonucleotide. 
     
     
         8 . The compound of  claim 1 , wherein the modified oligonucleotide is a chimeric oligonucleotide. 
     
     
         9 . The compound according to  claim 8 , wherein said chimeric oligonucleotide is 20 nucleotides in length, comprising ten 2′-deoxynucleotides, flanked on each side by five 2′-methoxyethyl nucleotides, wherein the internucleoside linkages are phosphorothioate, and all cytidine residues are 5-methylcytidines. 
     
     
         10 . The compound of  claim 1 , wherein at least a portion of said compound hybridizes with RNA to form an oligonucleotide-RNA duplex. 
     
     
         11 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 70% complementary within a nucleic acid molecule encoding diacylglycerol acyltransferase 1 (SEQ ID NO: 4). 
     
     
         12 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 80% complementary within a nucleic acid molecule encoding diacylglycerol acyltransferase 1 (SEQ ID NO: 4). 
     
     
         13 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary within a nucleic acid molecule encoding diacylglycerol acyltransferase 1 (SEQ ID NO: 4). 
     
     
         14 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 95% complementary within a nucleic acid molecule encoding diacylglycerol acyltransferase 1 (SEQ ID NO: 4). 
     
     
         15 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified sugar. 
     
     
         16 . The compound of  claim 15 , wherein the modified sugar comprises a 2′-O-methoxyethyl. 
     
     
         17 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         18 . The compound of  claim 1 , wherein the modified oligonucleotide comprises at least one modified nucleobase. 
     
     
         19 - 63 . (canceled) 
     
     
         64 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 99% complementary within a nucleic acid molecule encoding diacylglycerol acyltransferase 1 (SEQ ID NO: 4). 
     
     
         65 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary within a nucleic acid molecule encoding diacylglycerol acyltransferase 1 (SEQ ID NO: 4). 
     
     
         66 . The compound of  claim 15 , wherein the modified sugar is a bicyclic sugar. 
     
     
         67 . The compound of  claim 17 , wherein the modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         68 . The compound of  claim 18 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         69 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier or diluent.