Compositions and methods for inhibiting expression of transthyretin

Patent metadata

Field	Value
Publication number	US-12227744-B2
Application number	US-202217721704-A
Country	US
Kind code	B2
Filing date	Apr 15, 2022
Priority date	Oct 20, 2008
Publication date	Feb 18, 2025
Grant date	Feb 18, 2025

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.

First claim

The invention claimed is:

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.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Sah Dinah Wen-Yee
• Hinkle Gregory
• Alvarez Rene
• Milstein Stuart
• Chen Qingmin

Classifications

• C12N2320/30

  Special therapeutic applications · CPC title

• C12N2310/335

  Modified T or U · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• A61K31/713 Primary

  Double-stranded nucleic acids or oligonucleotides · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title