Modulation of apolipoprotein c-iii expression

Abstract

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

1 .- 60 . (canceled) 
     
     
         61 . A compound comprising a modified antisense oligonucleotide 15 to 30 nucleobases in length, wherein said modified antisense oligonucleotide specifically hybridizes within nucleotides 401-433, nucleotides 1065-1109, nucleotides 1267-1377, an intron, and exon:intron junction or an intron:exon junction of SEQ ID NO: 4. 
     
     
         62 . The compound of  claim 61 , wherein said compound comprises at least one modified internucleoside linkage, sugar moiety, or nucleobase. 
     
     
         63 . The compound of  claim 62 , wherein said modified internucleoside linkage is a phosphorothioate linkage. 
     
     
         64 . The compound of  claim 62 , wherein said modified sugar moiety is a 2′-O-methoxyethyl (2′-MOE), 2′-fluoro (2′-F) or 2′-methoxy (2′-O—CH 3 ) sugar moiety. 
     
     
         65 . The compound of  claim 62 , wherein said modified nucleobase is a 5-methylcytosine. 
     
     
         66 . The compound of  claim 61 , wherein said compound consists of a modified antisense oligonucleotide. 
     
     
         67 . The compound of  claim 61 , wherein said modified antisense oligonucleotide is fully complementary to SEQ ID NO: 4. 
     
     
         68 . The compound of  claim 61 , wherein said modified antisense oligonucleotide consists of 18, 19, 20, 21, or 22 linked nucleosides. 
     
     
         69 . The compound of  claim 61 , wherein said modified antisense oligonucleotide consists of 20 linked nucleosides. 
     
     
         70 . The compound of  claim 61 , wherein said compound demonstrates a reduction in apolipoprotein C-III mRNA levels of at least 45% when applied in vitro to cultured HepG2 cells at a concentration of 50 to 300 nM. 
     
     
         71 . The compound of  claim 61 , wherein said modified antisense oligonucleotide comprises a plurality of 2′-deoxynucleotides flanked on each side by at least one 2′-O-methoxyethyl nucleotide. 
     
     
         72 . The compound of  claim 61 , wherein said modified antisense oligonucleotide consists of: a gap segment consisting of ten linked 2′-deoxynucleosides; a 5′ wing segment consisting of five linked nucleosides; a 3′ wing segment consisting of five linked nucleosides; wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment, wherein each nucleoside of each wing segment comprises a 2′-O-methoxyethyl sugar moiety, and wherein each internucleoside linkage is a phosphorothioate linkage. 
     
     
         73 . The compound of  claim 72 , wherein said modified antisense oligonucleotide comprises at least one cytosine that is a 5-methylcytosine. 
     
     
         74 . The compound of  claim 73 , wherein each cytosine is a 5-methylcytosine. 
     
     
         75 . The compound of  claim 61 , wherein the modified antisense oligonucleotide is fully complementary to SEQ ID NO: 4. 
     
     
         76 . The compound of  claim 61 , wherein said modified antisense oligonucleotide comprises at least 8 consecutive nucleobases selected from the nucleobase sequence of SEQ ID NOs:19, 20, 22, 23, 25, 30, 31, 32, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 89, 90, 91, 92, 93, 94, 95, 96. 
     
     
         77 . The compound of  claim 61 , wherein said modified antisense oligonucleotide is in salt form. 
     
     
         78 . A composition comprising the compound of  claim 61  and a pharmaceutically acceptable carrier or diluent. 
     
     
         79 . The compound of  claim 61 , wherein said compound is single-stranded. 
     
     
         80 . The compound of  claim 61 , wherein said compound is double-stranded. 
     
     
         81 . The compound of  claim 61 , further comprising a conjugate group. 
     
     
         82 . The compound of  claim 61 , wherein said modified antisense oligonucleotide consists of the nucleobase sequence selected from SEQ ID NOs: 19, 20, 22, 23, 25, 30, 31, 32, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46, 47, 48, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 64, 65, 66, 67, 89, 90, 91, 92, 93, 94, 95, 96.