Antisense modulation of microsomal triglyceride transfer protein expression

Abstract

Antisense compounds, compositions and methods are provided for modulating the expression of microsomal triglyceride transfer protein. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding microsomal triglyceride transfer protein. Methods of using these compounds for modulation of microsomal triglyceride transfer protein expression and for treatment of diseases associated with expression of microsomal triglyceride transfer protein are provided.

1 . A compound 8 to 50 nucleobases in length targeted to a nucleic acid molecule encoding microsomal triglyceride transfer protein, wherein said compound specifically hybridizes with and inhibits the expression of a nucleic aid molecule encoding microsomal triglyceride transfer protein.  
     
     
         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: 17, 18, 19, 20, 22, 23, 32, 33, 47, 48, 49, 50, 51, 52, 53, 54, 57, 58, 59, 70, 71, 72, 73, 74, 77, 78, 79, 81, 82, 85, 88, 89, 91, 92, 93, 94, 95, 96, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137.  
     
     
         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 microsomal triglyceride transfer protein.  
     
     
         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 microsomal triglyceride transfer protein in cells or tissues comprising contacting said cells or tissues with the compound of  claim 1  so that expression of microsomal triglyceride transfer protein is inhibited.  
     
     
         16 . A method of treating an animal having a disease or condition associated with microsomal triglyceride transfer protein comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1  so that expression of microsomal triglyceride transfer protein 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.