Granted Patent
B2
US 12,227,744 · App. 17/721,704 · Granted Feb 18, 2025
Compositions and methods for inhibiting expression of transthyretin
Inventors:
Dinah Wen-Yee Sah (Boston, MA); Gregory Hinkle (Plymouth, MA); Rene Alvarez (Boxborough, MA); Stuart Milstein (Arlington, MA); Qingmin Chen (Lincoln, MA)
Assignee:
Alnylam Pharmaceuticals, Inc.
C12N15/113A61K9/0019A61K31/713C07F9/6533C07H21/04C12N15/111C12N2310/14C12N2310/315C12N2310/321C12N2310/335C12N2310/3515C12N2320/30C12N2320/32
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Abstract
The invention relates to a double-stranded ribonucleic acid (dsRNA) targeting a transthyretin (TTR) gene, and methods of using the dsRNA to inhibit expression of TTR.
Claims (11)
1. A pharmaceutical composition comprising a double-stranded ribonucleic acid (dsRNA) for inhibiting expression of transthyretin (TTR), wherein said dsRNA comprises a sense strand and an antisense strand forming a double stranded region, wherein each strand of the dsRNA is 19, 20, 21, 22, 23, or 24 nucleotides in length; wherein the antisense strand comprises 15 or more contiguous nucleotides of SEQ ID NO: 170, SEQ ID NO:450, SEQ ID NO:730, or SEQ ID NO: 1010; and a lipid formulation comprising a cationic lipid, a non-cationic lipid, and a polyethyleneglycol (PEG)-lipid.
2. The pharmaceutical composition of claim 1 , wherein the sense strand comprises 15 or more contiguous nucleotides of SEQ ID NO:169, SEQ ID NO:449, SEQ ID NO:729, or SEQ ID NO:1009.
3. The pharmaceutical composition of claim 1 , wherein the sense strand consists of SEQ ID NO:449 and the antisense strand consists of SEQ ID NO:450.
4. The pharmaceutical composition of claim 1 , wherein the sense strand consists of SEQ ID NO:729 and the antisense strand consists of SEQ ID NO:730.
5. The pharmaceutical composition of claim 1 , wherein the sense strand consists of SEQ ID NO: 1009 and the antisense strand consists of SEQ ID NO:1010.
6. The pharmaceutical composition of claim 1 , wherein the antisense strand comprises 15 or more contiguous nucleotides of SEQ ID NO: 170 and said dsRNA comprises at least one modified nucleotide.
7. The pharmaceutical composition of claim 6 , wherein at least one of said modified nucleotides is selected from the group consisting of a 2′-O-methyl modified nucleotide, a nucleotide comprising a 5′-phosphorothioate group, 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, a non-natural base comprising nucleotide, and a terminal nucleotide linked to a cholesteryl derivative or dodecanoic acid bisdecylamide group.
8. A method of inhibiting TTR expression in a cell, the method comprising: (a) contacting the cell with the pharmaceutical composition of claim 1 ; and (b) maintaining the cell produced in step (a) for a time sufficient to obtain degradation of the mRNA transcript of a TTR gene, thereby inhibiting the expression of the TTR gene in the cell.
9. The pharmaceutical composition of claim 1 , wherein the cationic lipid is (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) butanoate.
10. The pharmaceutical composition of claim 1 , wherein the non-cationic lipid is distearoylphosphatidylcholine (DSPC).
11. The pharmaceutical composition of claim 1 , wherein the formulation further comprises cholesterol.
Assignments (2)
SECURITY INTEREST
Recorded Oct 1, 2025
From: ALNYLAM PHARMACEUTICALS, INC.; SIRNA THERAPEUTICS, INC.
To: BANK OF AMERICA, N.A.
Reel/Frame 072996/0337 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 10, 2022
From: SAH, DINAH WEN-YEE; HINKLE, GREGORY; ALVAREZ, RENE; MILSTEIN, STUART; CHEN, QINGMIN
To: ALNYLAM PHARMACEUTICALS, INC.
Reel/Frame 059884/0283 →
Continuity (18)
Continuation
17475142
· Sep 14, 2021
Continuation
17360849
· Jun 28, 2021
Continuation
17234657
· Apr 19, 2021
Continuation
17102351
· Nov 23, 2020
Provisional Application
61244794
· Sep 22, 2009
Provisional Application
61242783
· Sep 15, 2009
Provisional Application
61185545
· Jun 9, 2009
Provisional Application
61156670
· Mar 2, 2009
Provisional Application
61115738
· Nov 18, 2008
Provisional Application
61106956
· Oct 20, 2008
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