MODULATION OF APOLIPOPROTEIN (a) EXPRESSION

Abstract

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

What is claimed is: 
     
         1 . A method of inhibiting apolipoprotein (a) (apo(a)) expression in an animal comprising administering to the animal a compound comprising a modified oligonucleotide 15-30 linked nucleosides in length targeted to apo(a), wherein expression of apo(a) is reduced by at least 30% in the animal. 
     
     
         2 . The method of  claim 1 , wherein reducing apo(a) expression in the animal
 (a) reduces Lp(a) levels;   (b) reduces cholesterol levels; and/or   (c) treats a cardiovascular disease.   
     
     
         3 . The method of  claim 1 , wherein the modified oligonucleotide has a nucleobase sequence at least 90%, at least 95% or 100% complementary to SEQ ID NO: 4, as measured over the entirety of said modified oligonucleotide. 
     
     
         4 . The method of  claim 1 , wherein the modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases selected from any of SEQ ID NOs: 12-14, 16-19, 21, 25, 30-36, 38, 41-43 or 45. 
     
     
         5 . The method of  claim 1 , wherein at least one internucleoside linkage of said modified oligonucleotide comprises a modified internucleoside linkage, at least one nucleoside of said modified oligonucleotide comprises a modified sugar and/or at least one nucleoside of said modified oligonucleotide comprises a modified nucleobase. 
     
     
         6 . The method of  claim 5 , wherein at least one internucleoside linkage comprises a phosphorothioate internucleoside linkage. 
     
     
         7 . The method of  claim 5 , wherein at least one modified sugar comprises a bicyclic sugar. 
     
     
         8 . The method of  claim 5 , wherein at least one modified sugar comprises a 2′-O-methoxyethyl. 
     
     
         9 . The method of  claim 5 , wherein the modified nucleobase is a 5-methylcytosine. 
     
     
         10 . The method of  claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         11 . The method of  claim 1 , wherein the modified oligonucleotide comprises:
 a. a gap segment consisting of linked deoxynucleosides;   b. a 5′ wing segment consisting of linked nucleosides; and   c. a 3′ wing segment consisting of linked nucleosides;   
       wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
     
     
         12 . The method of  claim 1 , wherein the modified oligonucleotide consists of 20 linked nucleosides and comprises:
 a. a gap segment consisting of ten linked deoxynucleosides;   b. a 5′ wing segment consisting of five linked nucleosides; and   c. 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, wherein at least one internucleoside linkage is a phosphorothioate linkage and wherein each cytosine residue is a 5-methylcytosine.   
     
     
         13 . The method of  claim 1 , wherein the apo(a) levels are reduced by at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, at least 85% or at least 90%. 
     
     
         14 . A compound comprising a modified oligonucleotide 15 to 30 linked nucleosides in length targeting apo(a) which comprises:
 a. a gap segment consisting of linked deoxynucleosides;   b. a 5′ wing segment consisting of linked nucleosides; and   c. a 3′ wing segment consisting of linked nucleosides;   
       wherein the gap segment is positioned between the 5′ wing segment and the 3′ wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. 
     
     
         15 . The compound of  claim 14 , wherein the modified oligonucleotide targeting apo(a) has a nucleobase sequence comprising at least 8 contiguous nucleobases selected from any of SEQ ID NOs: 12-14, 16-19, 21, 25, 30-36, 38, 41-43 or 45. 
     
     
         16 . The compound of  claim 14 , wherein the modified oligonucleotide has a nucleobase sequence at least 90%, at least 95% or 100% complementary to SEQ ID NO: 4, as measured over the entirety of said modified oligonucleotide. 
     
     
         17 . The compound of  claim 14 , wherein the modified sugar comprises a bicyclic sugar. 
     
     
         18 . The compound of  claim 14 , wherein the modified sugar comprises a 2′-O-methoxyethyl. 
     
     
         19 . The compound of  claim 14 , wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage. 
     
     
         20 . The compound of  claim 14 , further comprising a modified nucleobase. 
     
     
         21 . The compound of  claim 20 , wherein the modified nucleobase is a 5-methylcytosine.