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 at least one nucleobase selected from the group consisting of: 
 (a) C at position 27751 of SEQ ID NO: 1;    (b) C at position 27735 of SEQ ID NO: 1;    (c) G at position 27685 of SEQ ID NO: 1;    (d) G at position 27683 of SEQ ID NO: 1;    (e) G at position 27679 of SEQ ID NO: 1;    (f) A at position 27634 of SEQ ID NO: 1;    (g) T/U at position 27627 of SEQ ID NO: 1; or    (h) G at position 27618 of SEQ ID NO: 1, wherein G is guanine, C is cytosine, T is thymine, U is uracil, and A is adenine.    
     
     
         2 . The antisense compound of  claim 1  comprising at least one nucleobase selected from the group consisting of: 
 (a) G at position 15695 of SEQ ID NO: 2;    (b) G at position 15711 of SEQ ID NO: 2;    (c) C at position 15761 of SEQ ID NO: 2;    (d) C at position 15763 of SEQ ID NO: 2;    (e) C at position 15767 of SEQ ID NO: 2;    (f) T/U at position 15812 of SEQ ID NO: 2;    (g) A at position 15819 of SEQ ID NO: 2; or    (h) C at position 15828 of SEQ ID NO: 2, wherein G is guanine, C is cytosine, T is thymine, U is uracil, and A is adenine.    
     
     
         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 the antisense compound of  claim 1  so that expression of apolipoprotein B is inhibited.  
     
     
         15 . A method of screening for a modulator of apolipoprotein B, the method comprising the steps of: 
 contacting a preferred target segment of a nucleic acid molecule encoding apolipoprotein B with one or more candidate modulators of apolipoprotein B, and    identifying one or more modulators of apolipoprotein B expression which modulate the expression of apolipoprotein B, wherein said preferred target segment comprises at least one of:    (a) C at position 27751 of SEQ ID NO: 1;    (b) C at position 27735 of SEQ ID NO: 1;    (c) G at position 27685 of SEQ ID NO: 1;    (d) G at position 27683 of SEQ ID NO: 1;    (e) G at position 27679 of SEQ ID NO: 1;    (f) A at position 27634 of SEQ ID NO: 1;    (g) T/U at position 27627 of SEQ ID NO: 1; or    (h) G at position 27618 of SEQ ID NO: 1, wherein G is guanine, C is cytosine, T is thymine, U is uracil, and A is adenine.    
     
     
         16 . The method of  claim 15  wherein the modulator of apolipoprotein B expression comprises an oligonucleotide, an antisense oligonucleotide, a DNA oligonucleotide, an RNA oligonucleotide, an RNA oligonucleotide having at least a portion of said RNA oligonucleotide capable of hybridizing with RNA to form an oligonucleotide-RNA duplex, or a chimeric oligonucleotide.  
     
     
         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 the antisense compound of  claim 1  so that expression of apolipoprotein B is inhibited.  
     
     
         18 . The method of claim  21  wherein the disease or condition is a disorder of lipid metabolism.