Compositions and their uses directed to hepcidin

Abstract

Disclosed herein are compounds, compositions and methods for modulating the expression of hepcidin in a cell, tissue or animal or preventing, ameliorating or treating anemia. Also provided are methods for prevention, amelioration or treatment of anemia, and for increasing red blood cell count in an animal. Also provided are methods for the prevention, amelioration and/or treatment of low serum iron levels, low red blood cell count and other clinical endpoints of anemia in an animal. These methods may be achieved by administration of compounds or compositions including antisense compounds targeted to a nucleic acid that expresses hepcidin polypeptide combined with an erythropoiesis stimulating agent.

1 . A compound comprising a modified oligonucleotide consisting of 12 to 35 linked nucleosides and having a nucleobase sequence comprising at least 8 contiguous nucleobases complementary to an equal length portion of a nucleobase sequence of a nucleic acid encoding hepcidin, wherein said modified oligonucleotide specifically hybridizes to said nucleic acid encoding hepcidin. 
     
     
         2 . The compound of  claim 1 , wherein said nucleobase sequence of a nucleic acid encoding hepcidin is selected from the group consisting of SEQ ID NOs: 1, 2 and 3. 
     
     
         3 . The compound of  claim 2 , wherein said nucleobase sequence of a nucleic acid encoding hepcidin is SEQ ID NO: 1. 
     
     
         4 . The compound of  claim 3 , wherein said modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases complementary to an equal length portion of nucleotides 123-566 of SEQ ID NO: 1. 
     
     
         5 . The compound of  claim 3 , wherein said modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases complementary to an equal length portion of nucleotides 442-541 of SEQ ID NO: 1. 
     
     
         6 . The compound of  claim 3 , wherein said compound consists of a single-stranded modified oligonucleotide. 
     
     
         7 . The compound of  claim 1 , wherein the nucleobase sequence of the modified oligonucleotide is at least 90% complementary to at least a 20 contiguous nucleobase portion of nucleotides 123-566 of SEQ ID NO: 1. 
     
     
         8 . The compound of  claim 6 , wherein the nucleobase sequence of the modified oligonucleotide is 100% complementary to at least a 20 contiguous nucleobase portion of nucleotides 123-566 of SEQ ID NO: 1. 
     
     
         9 . The compound of  claim 6 , wherein at least one internucleoside linkage of said modified oligonucleotide is a modified internucleoside linkage. 
     
     
         10 . The compound of  claim 9 , wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate internucleoside linkage. 
     
     
         11 . The compound of  claim 6 , wherein at least one nucleoside of said modified oligonucleotide comprises a modified sugar. 
     
     
         12 . The compound of  claim 11 , wherein at least one modified sugar is a bicyclic sugar. 
     
     
         13 . The compound of  claim 11 , wherein at least one modified sugar is selected from the group consisting of a 2′-O-(2-methoxyethyl), and a 4′-(CH 2 ) 2 —O-2′ bridge, wherein n is 1 or 2. 
     
     
         14 . The compound of  claim 6 , wherein at least one nucleoside of said modified oligonucleotide comprises a modified nucleobase. 
     
     
         15 . The compound of  claim 14 , wherein said modified nucleobase is a 5-methylcytosine. 
     
     
         16 . The compound of  claim 3 , wherein said modified oligonucleotide comprises:
 a gap segment consisting of linked deoxynucleosides;   a 5′ wing segment consisting of linked nucleosides; and   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.   
     
     
         17 . The compound of  claim 16 , wherein said modified oligonucleotide comprises:
 a gap segment consisting of ten linked deoxynucleosides;   a 5′ wing segment consisting of five linked nucleosides; and   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 each cytosine in said modified oligonucleotide is a 5-methylcytosine, and wherein each internucleoside linkage of said modified oligonucleotide is a phosphorothioate linkage.   
     
     
         18 . The compound of  claim 17 , wherein said modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         19 . The compound of  claim 6 , wherein said modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         20 . A composition comprising the compound of  claim 3  or a salt thereof and a pharmaceutically acceptable carrier or diluent. 
     
     
         21 . The composition of  claim 20 , wherein said compound consists of a single-stranded modified oligonucleotide. 
     
     
         22 . The composition of  claim 20 , wherein said modified oligonucleotide consists of 20 linked nucleosides. 
     
     
         23 . The compound of  claim 1 , wherein said modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases complementary to an equal length portion of a nucleotide region selected from the group consisting of nucleotides 123-566, 123-252, 295-566, 352-405, 429-566, and 456-527 of SEQ ID NO: 1, 204-341 and 231-302 of SEQ ID NO: 2, and 3249-4743, 3249-3454, 3398-3454, 4643-4703, and 4643-4743 of SEQ ID NO: 3. 
     
     
         24 . The compound of  claim 1 , wherein said modified oligonucleotide has a nucleobase sequence comprising at least 8 contiguous nucleobases of a nucleobase sequence selected from the group consisting of SEQ ID NOs: 23-37. 
     
     
         25 . The compound of  claim 1 , wherein said modified oligonucleotide has a nucleobase sequence consisting of a nucleobase sequence selected from the group consisting of SEQ ID NOs: 23-37.