Compositions and methods directed to treating liver fibrosis
AssigneeAlnylam Pharmaceuticals, Inc.
InventorsGreg Hinkle, Victor Kotelianski, Brian Bettencourt, Alfica Sehgal, Tatiana Novobrantseva
Life of this patent
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Abstract
The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the COL1A1, TGF-β, and SMAD2/3 genes, and methods of using such dsRNA compositions to inhibit expression of COL1A1, TGF-β, and SMAD2/3.
Claims40
A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of COL1A1, wherein said dsRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:
- 53 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the corresponding antisense nucleotide sequence of SEQ ID NO:
- 54.
A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of COL1A1, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a COL1A1 RNA transcript, which antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences of SEQ ID NOs:
- 1-62 or SEQ ID NOs:
- 185-2792.
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A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of TGFβ, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a TGFβ RNA transcript, which antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences of SEQ ID NOs:
- 63-130 or SEQ ID NOs:
- 2793-2860.
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A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of SMAD2/3, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a SMAD2/3 RNA transcript, which antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences of SEQ ID NOs:
- 132-167.
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A method of inhibiting COL1A1 expression in a cell, the method comprising:
- a. introducing into the cell a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of COL1A1, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a COL1A1 RNA transcript, which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences of SEQ ID NOs:
- 1-62 or SEQ ID NOs:
- 185-2792;
- and
- b. maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a COL1A1 gene, thereby inhibiting expression of the COL1A1 gene in the cell.
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A method of treating liver fibrosis comprising administering to a human in need of such treatment a therapeutically effective amount of a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of COL1A1, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a COL1A1 RNA transcript, which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences of SEQ ID NOs:
- 1-62 or SEQ ID NOs:
- 185-2792 or a pharmaceutical composition thereof.
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A vector encoding at least one strand of a dsRNA, wherein said dsRNA comprises a region of complementarity to at least a part of an mRNA encoding COL1A1, wherein said dsRNA is base pairs or less in length, and wherein said dsRNA targets a said mRNA for cleavage.
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A method of treating a chronic liver disease characterized by liver fibrosis comprising administering to a human in need of such treatment a therapeutically effective amount of a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of COL1A1, wherein said dsRNA comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity to a COL1A1 RNA transcript, which comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from one of the antisense sequences of SEQ ID NOs:
- 1-62 or SEQ ID NOs:
- 185-2792 or a pharmaceutical composition thereof.
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Dependencies are inferred from the claim text.