Antisense modulation of acyl coa cholesterol acyltransferase-2 expression

Abstract

Antisense compounds, compositions and methods are provided for modulating the expression of acyl CoA cholesterol acyltransferase-2. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding acyl CoA cholesterol acyltransferase-2. Methods of using these compounds for modulation of acyl CoA cholesterol acyltransferase-2 expression and for treatment of diseases associated with expression of acyl CoA cholesterol acyltransferase-2 are provided.

1 . A compound 8 to 50 nucleobases in length targeted to a nucleic acid molecule encoding acyl CoA cholesterol acyltransferase-2, wherein said compound specifically hybridizes with and inhibits the expression of a nucleic acid molecule encoding acyl CoA cholesterol acyltransferase-2. 
     
     
         2 . The compound of  claim 1  which is an antisense oligonucleotide. 
     
     
         3 . The compound of  claim 2  wherein the antisense oligonucleotide has a sequence comprising SEQ ID NO: 21, 23, 24, 25, 26, 28, 29, 30, 31, 33, 34, 35, 36, 37, 38, 42, 43, 46, 47, 48, 49, 54, 55, 56, 57, 58, 62, 63 or 65. 
     
     
         4 . The compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage. 
     
     
         5 . The compound of  claim 4  wherein the modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         6 . The compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified sugar moiety. 
     
     
         7 . The compound of  claim 6  wherein the modified sugar moiety is a 2′-O-methoxyethyl sugar moiety. 
     
     
         8 . The compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified nucleobase. 
     
     
         9 . The compound of  claim 8  wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         10 . The compound of  claim 2  wherein the antisense oligonucleotide is a chimeric oligonucleotide. 
     
     
         11 . A compound 8 to 50 nucleobases in length which specifically hybridizes with at least an 8-nucleobase portion of an active site on a nucleic acid molecule encoding acyl CoA cholesterol acyltransferase-2. 
     
     
         12 . A composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         13 . The composition of  claim 12  further comprising a colloidal dispersion system. 
     
     
         14 . The composition of  claim 12  wherein the compound is an antisense oligonucleotide. 
     
     
         15 . A method of inhibiting the expression of acyl CoA cholesterol acyltransferase-2 in cells or tissues comprising contacting said cells or tissues with the compound of  claim 1  so that expression of acyl CoA cholesterol acyltransferase-2 is inhibited. 
     
     
         16 . A method of treating an animal having a disease or condition associated with acyl CoA cholesterol acyltransferase-2 comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1  so that expression of acyl CoA cholesterol acyltransferase-2 is inhibited. 
     
     
         17 . The method of  claim 16  wherein the condition involves abnormal lipid metabolism. 
     
     
         18 . The method of  claim 16  wherein the condition involves abnormal cholesterol metabolism. 
     
     
         19 . The method of  claim 16  wherein the condition is atherosclerosis. 
     
     
         20 . The method of  claim 16  wherein the disease is cardiovascular disease.