Compositions and methods for inhibiting expression of the HAMP gene
View Patent ↗The invention relates to a double-stranded ribonucleic acid (dsRNA) for inhibiting the expression of the HAMP gene (HAMP gene), comprising an antisense strand having a nucleotide sequence which is less that 30 nucleotides in length, generally 19-25 nucleotides in length, and which is substantially complementary to at least a part of the HAMP gene. The invention also relates to a pharmaceutical composition comprising the dsRNA together with a pharmaceutically acceptable carrier; methods for treating diseases caused by HAMP gene expression and the expression of the HAMP gene using the pharmaceutical composition.
1. A method of inhibiting the expression of hepcidin antimicrobial peptide (HAMP) in a cell or tissue, comprising contacting the cell or tissue with a compound comprising an antisense strand and a sense strand that are each equal to or less than 30 nucleotides in length, wherein the compound is targeted to a nucleic acid molecule encoding HAMP and comprising the first nineteen nucleotides of SEQ ID NO:29 (GAACAUAGGUCUUGGAAUA), and wherein the compound specifically hybridizes with a 5′ untranslated region or coding region of the nucleic acid molecule, so that expression of HAMP is inhibited by at least 20%.
2. The method of claim 1 , wherein the compound comprises at least one modified nucleotide.
3. The method of claim 2 , wherein the modified nucleotide is chosen from the group 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.
4. The method of claim 2 , wherein the modified nucleotide is chosen from the group of: 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.
5. The method of claim 1 , wherein the sense strand is modified as follows: GAAcAuAGGucuuGGAAuATsT (SEQ ID NO:227) and the antisense strand is modified as follows: uAuUCcAAGACCuAuGuUCTs (SEQ ID NO:244), wherein “c” indicates a 2′-O-methyl modified cytodine; “u” indicates a 2′-O-methyl modified uracil, and sT indicates a 5′-phosphorothioate modified thymidine.
6. The method of claim 1 , wherein the sense strand consists of SEQ ID NO:29 and the antisense strand consists of SEQ ID NO:65.
7. The method of claim 1 , wherein the sense strand comprises SEQ ID NO:29 and the antisense strand comprises SEQ ID NO:65.
8. The method of claim 1 , wherein the compound is formulated in a lipid formulation.
9. The method of claim 1 , wherein the compound is formulated in a liposome.
10. The method of claim 1 , wherein the compound is conjugated to a molecule.
11. The method of claim 10 , wherein the molecule is a ligand moiety or a non-ligand moiety.
12. The method of claim 1 , wherein the cell or tissue is human.
13. The method of claim 1 , wherein the expression of HAMP is inhibited by at least 60%.
14. The method of claim 1 , wherein the expression of HAMP is inhibited by at least 70%.
15. The method of claim 1 , wherein the expression of HAMP is inhibited by at least 80%.
16. The method of claim 1 , wherein the expression of HAMP is inhibited by at least 90%.
17. The method of claim 1 , wherein the compound specifically hybridizes with the 5′ untranslated region of the nucleic acid molecule.
18. The method of claim 1 , wherein the compound specifically hybridizes with the coding region of the nucleic acid molecule.
19. The method of claim 1 , wherein each strand is 21 nucleotides or less in length.
20. A compound for inhibiting the expression of hepcidin antimicrobial peptide (HAMP) in a cell or tissue, comprising an antisense strand and a sense strand that are each equal to or less than 30 nucleotides in length, wherein the compound is targeted to a nucleic acid molecule encoding HAMP and comprising the first nineteen nucleotides of SEQ ID NO:29 (GAACAUAGGUCUUGGAAUA), and wherein the compound specifically hybridizes with a 5′ untranslated region or coding region of the nucleic acid molecule, so that expression of HAMP is inhibited by at least 20%.