Compositions and methods for inhibiting expression of the ALAS1 gene
AssigneesAlnylam Pharmaceuticals, Inc., Icahn School of Medicine at Mount Sinai
InventorsBrian Bettencourt, Kevin Fitzgerald, William Querbes, Robert J. Desnick, Makiko Yasuda
Life of this patent
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Abstract
The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting the ALAS1 gene, and methods of using such dsRNA compositions to alter (e.g., inhibit) expression of ALAS1.
Claims58
A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ALAS1, wherein said dsRNA comprises a sense strand and an antisense strand, wherein:
- (i) the antisense strand is complementary to at least nucleotides 871-889 of SEQ ID NO:1 and comprises SEQ ID NO:1296,
- (ii) the sense strand comprises at least 15 contiguous nucleotides from SEQ ID NO:1295,
- (iii) a ligand and linker with a structure as shown below is attached to the 3′ end of the sense strand of the dsRNA
- and
- (iv) the dsRNA comprises one or more nucleotides with a modification chosen from a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, or both.
A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ALAS1, comprising:
- (i) an antisense strand complementary to at least nucleotides 871-889 of SEQ ID NO:1;
- (ii) a sense strand comprising at least 15 contiguous nucleotides from SEQ ID NO:1295;
- (iii) one or more N-acetylgalactosamine (GalNAc) derivatives;
- and
- (iv) one or more nucleotides with a modification chosen from a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, or both.
The dsRNA of 3, wherein the one or more GalNAc derivatives is a biantennary or a triantennary GalNAc ligand.
The dsRNA of 22, wherein the GalNAc ligand is:
The dsRNA of 23, wherein the GalNAc ligand is attached to the 3′ end of the sense strand.
The dsRNA of 23, wherein the GalNAc ligand is attached to the 3′ end of the sense strand via linker.
The dsRNA of 22, wherein GalNAc ligand and linker have the structure of:
A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ALAS1, comprising:
- (i) an antisense strand that comprises the sequence of SEQ ID NO:1296;
- (ii) a sense strand comprising at least 15 contiguous nucleotides from SEQ ID NO:1295;
- (iii) a duplex region of 15-30 base pairs in length;
- (iv) a biantennary or a triantennary GalNAc ligand;
- (v) 20 or more modified nucleotides chosen from 2′-O-methyl modified nucleotides and 2′-fluoro modified nucleotides;
- and
- (vi) at least one strand comprising a 3′ overhang of at least 1 nucleotide.
The dsRNA of 33, wherein the GalNAc ligand is:
The dsRNA of 36, wherein the GalNAc ligand is attached to the 3′ end of the sense strand.
The dsRNA of 36, wherein the GalNAc ligand is attached to the 3′ end of the sense strand via linker.
The dsRNA of 38, wherein GalNAc ligand and linker have the structure of:
A double-stranded ribonucleic acid (dsRNA) for inhibiting expression of ALAS1, comprising:
- (i) an antisense strand that is fully complementary to at least nucleotides 871-889 of SEQ ID NO:1;
- (ii) a sense strand comprising at least 15 contiguous nucleotides from SEQ ID NO:1295, wherein each of the sense strand and the antisense strand are 19-24 nucleotides in length;
- (iii) a ligand attached to the 3′ end of the sense strand and having the structure:
- (iv) modified nucleotides over the entire length of the sense strand and the antisense strand consisting of 2′-O-methyl modified nucleotides, 2′-fluoro modified nucleotides, and phosphorothioate linkages;
- (v) the antisense strand comprising a 3′-overhang of 2 nucleotides in length;
- and
- (vi) a blunt-ended sense strand.
Dependencies are inferred from the claim text.