SNPs OF APOLIPOPROTEIN B AND MODULATION OF THEIR EXPRESSION

Abstract

Compounds, compositions and methods are provided for modulating the expression of apolipoprotein B. The compositions comprise oligonucleotides, targeted to nucleic acid encoding apolipoprotein B. Methods of using these compounds for modulation of apolipoprotein B expression and for diagnosis and treatment of diseases and conditions associated with expression of apolipoprotein B are provided.

1 . An antisense compound 15 to 30 nucleobases in length which specifically hybridizes with an allelic variant of a nucleic acid of SEQ ID NO: 1 encoding human apolipoprotein B, wherein said compound inhibits the expression of apolipoprotein B mRNA by at least 10% and wherein said compound is targeted to a region that includes a cytosine (C) at position 27735 of SEQ ID NO: 1. 
     
     
         2 . The antisense compound of  claim 1  comprising a guanine (G) at position 15711 of SEQ ID NO: 2. 
     
     
         3 . The antisense compound of  claim 1  which is 20 nucleobases in length. 
     
     
         4 . The antisense compound of  claim 1  comprising an oligonucleotide. 
     
     
         5 . The antisense compound of  claim 4  comprising a DNA oligonucleotide. 
     
     
         6 . The antisense compound of  claim 4  comprising an RNA oligonucleotide. 
     
     
         7 . The antisense compound of  claim 4  comprising a chimeric oligonucleotide. 
     
     
         8 . The antisense compound of  claim 4  wherein at least a portion of said compound hybridizes with RNA to form an oligonucleotide-RNA duplex. 
     
     
         9 . The antisense compound of  claim 1  having at least 80%, at least 85%, at least 90% or, at least 95% or at least 99% complementarity with said nucleic acid molecule encoding apolipoprotein B. 
     
     
         10 . The antisense compound of  claim 1  having one, two or more types of modifications, wherein the modification comprises a modified internucleoside linkage, sugar moiety, or nucleobase. 
     
     
         11 . The antisense compound of  claim 1  having at least one 2′-O-methoxyethyl sugar moiety. 
     
     
         12 . The antisense compound of  claim 1  having at least one phosphorothioate internucleoside linkage. 
     
     
         13 . The antisense compound of  claim 1  wherein at least one cytosine is a 5-methylcytosine. 
     
     
         14 . A method of inhibiting the expression of apolipoprotein B in a cell or tissue comprising contacting said cell or tissue with an antisense compound so that expression of apolipoprotein B is inhibited, wherein the antisense compound is an antisense compound 15 to 30 nucleobases in length which specifically hybridizes with an allelic variant of a nucleic acid of SEQ ID NO: 1 encoding human apolipoprotein B, wherein said compound inhibits the expression of apolipoprotein B mRNA by at least 10% and wherein said compound is targeted to a region that includes a cytosine (C) at position 27735 of SEQ ID NO: 1. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . 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 an antisense compound so that expression of apolipoprotein B is inhibited, wherein the antisense compound is an antisense compound 15 to 30 nucleobases in length which specifically hybridizes with an allelic variant of a nucleic acid of SEQ ID NO: 1 encoding human apolipoprotein B, wherein said compound inhibits the expression of apolipoprotein B mRNA by at least 10% and wherein said compound is targeted to a region that includes a cytosine (C) at position 27735 of SEQ ID NO: 1. 
     
     
         18 . The method of  claim 17  wherein the disease or condition is a disorder of lipid metabolism. 
     
     
         19 . The antisense compound of  claim 7 , wherein the antisense compound is a chimeric oligonucleotide consisting of:
 a gap segment consisting of from 10 to 18 linked 2′-deoxynucleosides;   a 5′ wing segment consisting of from 1 to 5 linked nucleosides; and   a 3′ wing segment consisting of from 1 to 5 linked nucleosides;   
       wherein each nucleoside of the 5′ wing segment is a sugar-modified nucleoside, each nucleoside of the 3′ wing segment is a sugar-modified nucleoside, and each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         20 . The antisense compound of  claim 19 , wherein the sugar modification is a 2′-O-methoxyethyl sugar modification. 
     
     
         21 . The antisense compound of  claim 7  wherein the antisense compound is a chimeric oligonucleotide consisting of:
 a gap segment consisting of ten linked 2′-deoxynucleosides; 
 a 5′ wing segment consisting of five linked nucleosides; and 
 a 3′ wing segment consisting of five linked nucleosides; 
 
       wherein each nucleoside of the 5′ wing segment is a 2′-O-methoxyethyl nucleoside, each nucleoside of the 3′ wing segment is a 2′-O-methoxyethyl nucleoside, and each internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         22 . The antisense compound of  claim 21  comprising at least one cytosine, wherein the cytosine is a 5-methylcytosine. 
     
     
         23 . A pharmaceutical composition comprising the antisense compound of  claim 1  and pharmaceutically acceptable excipient. 
     
     
         24 . A pharmaceutical composition comprising the antisense compound of  claim 19  and pharmaceutically acceptable excipient. 
     
     
         25 . A pharmaceutical composition comprising the antisense compound of  claim 21  and pharmaceutically acceptable excipient. 
     
     
         26 . A pharmaceutical composition comprising the antisense compound of  claim 22  and pharmaceutically acceptable excipient. 
     
     
         27 . The antisense compound of  claim 19 , wherein the gap segment is flanked on both the 5′ and 3′ sides by wing segments of the same length. 
     
     
         28 . The antisense compound of  claim 19 , wherein the gap segment is flanked on both the 5′ and 3′ sides by wing segments of different lengths. 
     
     
         29 . The antisense compound of  claim 27 , wherein the antisense compound is 20 nucleobases in length, and wherein:
 (i) the gap segment is 8 nucleotides in length, and the 5′ and 3′ wing segments are each 6 nucleotides in length;   (ii) the gap segment is 10 nucleotides in length, and the 5′ and 3′ wing segments are each 5 nucleotides in length;   (iii) the gap segment is 12 nucleotides in length, and the 5′ and 3′ wing segments are each 4 nucleotides in length;   (iv) the gap segment is 14 nucleotides in length, and the 5′ and 3′ wing segments are each 3 nucleotides in length;   (v) the gap segment is 16 nucleotides in length, and the 5′ and 3′ wing segments are each 2 nucleotides in length; or   (vi) the gap segment is 18 nucleotides in length, and the 5′ and 3′ wing segments are each 1 nucleotide in length.   
     
     
         30 . The antisense compound of  claim 28 , wherein the antisense compound is 20 nucleobases in length, and wherein the gap segment is 10 nucleotides in length, flanked on one side by a wing segment 6 nucleotides in length and flanked on the other side by a wing segment 4 nucleotides in length.