Antisense modulation of apolipoprotein b expression

Abstract

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

1 . A compound 8 to 50 nucleobases in length targeted to a nucleic acid molecule encoding apolipoprotein B, wherein said compound specifically hybridizes with and inhibits the expression of a nucleic acid molecule encoding apolipoprotein B. 
     
     
         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, 21, 23, 24, 25, 27, 28, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 45, 46, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, 61, 62, 63, 66, 67, 69, 71, 73, 74, 75, 76, 78, 79, 81, 82, 83, 84, 86, 87, 88, 90, 93, 96, 101, 101, 102, 103, 105, 109, 111, 111, 114, 115, 116, 117, 118, 119, 120, 121 or 122. 
     
     
         4 . The compound of  claim 2  wherein the antisense oligonucleotide comprises at least one modified internucleoside linkage, at least one modified sugar moiety, or at least one modified nucleobase. 
     
     
         5 . The compound of  claim 4  wherein the modified internucleoside linkage is a phosphorothioate linkage; (ii) the modified sugar moiety is a 2′-O-methoxyethyl sugar moiety; or (iii) the modified nucleobase is a 5-methylcytosine. 
     
     
         6 .- 9 . (canceled) 
     
     
         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 apolipoprotein B. 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . A method of inhibiting the expression of apolipoprotein B in cells or tissues comprising contacting said cells or tissues with the compound of  claim 1  so that expression of apolipoprotein B is inhibited. 
     
     
         16 . A method of treating an animal having a disease or condition associated with apolipoprotein B comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1  so that expression of apolipoprotein B is inhibited. 
     
     
         17 . The method of  claim 16  wherein the condition involves abnormal lipid metabolism the condition involves abnormal cholesterol metabolism; or the condition is atherosclerosis. 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The compound of  claim 1  targeted to a nucleic acid molecule encoding apolipoprotein B, wherein said compound specifically hybridizes with and inhibits the expression of the long form of a nucleic acid molecule encoding apolipoprotein B, ApoB-100. 
     
     
         21 . The method of  claim 16  wherein the condition is an abnormal metabolic condition, hyperlipidemia, diabetes, Type 2 diabetes, obesity, atherosclerosis, or a cardiovascular disease. 
     
     
         22 .- 27 . (canceled) 
     
     
         28 . A method of modulating glucose levels in an animal comprising administering to said animal the compound of  claim 1 . 
     
     
         29 .- 32 . (canceled) 
     
     
         33 . A method of preventing or delaying the onset of a disease or condition associated with apolipoprotein B in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1 . 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 33  wherein the condition is an abnormal metabolic condition, hyperlipidemia, diabetes, Type 2 diabetes, obesity, atherosclerosis, or wherein the condition involves abnormal lipid metabolism or abnormal cholesterol metabolism. 
     
     
         36 .- 42 . (canceled) 
     
     
         43 . A method of preventing or delaying the onset of an increase in glucose levels in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1 . 
     
     
         44 .- 46 . (canceled) 
     
     
         47 . A method of modulating serum cholesterol levels in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1 . 
     
     
         48 . (canceled) 
     
     
         49 . A method of modulating lipoprotein levels in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1 . 
     
     
         50 . (canceled) 
     
     
         51 . The method of  claim 49  wherein the lipoprotein is VLDL, HDL or LDL. 
     
     
         52 . (canceled) 
     
     
         53 . (canceled) 
     
     
         54 . A method of modulating serum triglyceride levels in an animal comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of  claim 1 . 
     
     
         55 . (canceled) 
     
     
         56 . (canceled)