Compositions and methods for inhibiting hepcidin antimicrobial peptide (HAMP) or HAMP-related gene expression

Abstract

The invention relates to lipid formulated double-stranded ribonucleic acid (dsRNA) targeting a hepcidin antimicrobial peptide (HAMP) and/or HAMP-related gene, and methods of using the dsRNA to inhibit expression of HAMP and/or HAMP-related genes.

1 . A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of hepcidin antimicrobial peptide (HAMP), wherein said dsRNA is selected from the dsRNAs listed in Table 2, 3, 4, or 5 with a start position of 382, 380, 379, or 385. 
     
     
         2 . The dsRNA of  claim 1 , wherein the dsRNA consists of AD-48141, wherein the sense strand of AD-48141 is GAAcAuAGGucuuGGAAuAdTdT and the antisense strand of AD-48141 is UAuUCcAAGACCuAuGuUCdTdT. 
     
     
         3 . A dsRNA for inhibiting expression of HAMP, wherein said dsRNA comprises a sense strand and an antisense strand, wherein each strand is 30 nucleotides in length or less, and wherein the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense strand sequences listed in Table 2, 3, 4, or 5. 
     
     
         4 .- 13 . (canceled) 
     
     
         14 . The dsRNA of  claim 3 , wherein the sense strand comprises one of the sense strand sequences of Table 2, 3, 4, or 5 and the antisense strand comprises one of the antisense strand sequences of Table 2, 3, 4, or 5. 
     
     
         15 . The dsRNA of  claim 3 , wherein the sense strand consists of one of the sense strand sequences of Table 2, 3, 4, or 5 and the antisense strand consists of one of the antisense strand sequences of Table 2, 3, 4, or 5. 
     
     
         16 . (canceled) 
     
     
         17 . The dsRNA of  claim 3 , wherein said dsRNA further comprises at least one modified nucleotide. 
     
     
         18 . The dsRNA of  claim 17 , wherein at least one of said modified nucleotides is chosen from the group consisting of: a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group. 
     
     
         19 . The dsRNA of  claim 17 , wherein said modified nucleotide is chosen from the group consisting of: a 2′-fluoro modified nucleotide, a 2′-fluoro modified nucleoside, a 2′-deoxy-2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, 2′-amino-modified nucleotide, 2′-alkyl-modified nucleotide, morpholino nucleotide, a phosphoramidate, and a non-natural base comprising nucleotide. 
     
     
         20 .- 23 . (canceled) 
     
     
         24 . The dsRNA of  claim 3 , further comprising a ligand. 
     
     
         25 . The dsRNA of  claim 24 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA. 
     
     
         26 . The dsRNA of  claim 3 , further comprising an N-Acetyl-Galactosamine (GalNac) conjugate. 
     
     
         27 . The dsRNA of  claim 3 , wherein the dsRNA is formulated in a nucleic acid lipid particle formulation. 
     
     
         28 . The dsRNA of  claim 27 , wherein the nucleic acid lipid particle formulation is selected from Table A. 
     
     
         29 . The dsRNA of  claim 27 , wherein the nucleic acid lipid particle formulation comprises MC3. 
     
     
         30 .- 32 . (canceled) 
     
     
         33 . A pharmaceutical composition for inhibiting expression of a HAMP gene comprising the dsRNA of  claim 3 . 
     
     
         34 .- 103 . (canceled) 
     
     
         104 . A method of inhibiting HAMP expression in a cell, the method comprising:
 (a) contacting the cell the dsRNA of  claim 3 ; and   (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a HAMP gene, thereby inhibiting expression of the HAMP gene in the cell.   
     
     
         105 . (canceled) 
     
     
         106 . The method of  claim 104 , wherein the HAMP expression is inhibited by at least 30% or at least 80%. 
     
     
         107 . A method of treating a disorder associated with HAMP expression comprising administering to a subject in need of such treatment a therapeutically effective amount of the dsRNA of  claim 3 . 
     
     
         108 .- 110 . (canceled) 
     
     
         111 . The method of  claim 107 , wherein the subject has anemia, refractory anemia, anemia of chronic disease (ACD), or iron-restricted erythropoiesis. 
     
     
         112 . (canceled) 
     
     
         113 . The method of  claim 107 , wherein the dsRNA is administered at a concentration of 0.01 mg/kg-5 mg/kg bodyweight of the subject. 
     
     
         114 .- 272 . (canceled)