IP Library › Granted Patent US 11,649,461
Granted Patent B2
US 11,649,461 · App. 16/570,351 · Granted May 16, 2023

Polynucleotides encoding α-galactosidase A for the treatment of Fabry disease

Inventors: Paolo Martini (Cambridge, MA); Stephen G. Hoge (Brookline, MA); Kerry Benenato (Sudbury, MA); Vladimir Presnyak (Manchester, NH); Iain Mcfadyen (Arlington, MA); Ellalahewage Sathyajith Kumarasinghe (Harvard, MA); Xuling Zhu (Cambridge, MA); Lin Tung Guey (Cambridge, MA); Staci Sabnis (Cambridge, MA)
Assignee: ModernaTX, Inc.
C12N15/67A61K9/5123A61K38/47A61P3/00C12N9/2465C12Y302/01022A61K48/00
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Quick Facts
Patent No.
US 11,649,461
App. No.
16/570,351
Granted
May 16, 2023
Kind
B2
Abstract

The invention relates to mRNA therapy for the treatment of Fabry disease. mRNAs for use in the invention, when administered in vivo, encode human the α-galactosidase A (GLA), isoforms thereof, functional fragments thereof, and fusion proteins comprising GLA. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to effect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of GLA expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient GLA activity in subjects, namely Gb3 and lyso-Gb3.

Claims (21)

1. A lipid nanoparticle, comprising (i) an mRNA comprising an ORF encoding a human GLA polypeptide, wherein the mRNA comprises a nucleotide sequence at least 95% identical to SEQ ID NO: 79, and (ii) an ionizable lipid, wherein the ionizable lipid is a compound selected from Compound 1 to Compound 232, salts and stereoisomers thereof, and combinations thereof.

2. The lipid nanoparticle of claim 1 , wherein the compound is selected from Compound 1 to Compound 147, salts and stereoisomers thereof, and combinations thereof.

3. The lipid nanoparticle of claim 2 , wherein the compound is Compound 18, a salt or a stereoisomer thereof, or any combination thereof.

4. The lipid nanoparticle of claim 1 , comprising from about 45 mol % to about 55 mol % of ionizable lipid.

5. The lipid nanoparticle of claim 1 , comprising from about 1 mol % to about 20 mol % of phospholipid.

6. The lipid nanoparticle of claim 1 , comprising from about 35 mol % to about 40 mol % of structural lipid.

7. The lipid nanoparticle of claim 1 , comprising from about 2 mol % to about 4 mol % of PEG lipid.

8. A lipid nanoparticle, comprising (i) an mRNA comprising an ORF encoding a human GLA polypeptide, wherein the mRNA comprises a nucleotide sequence at least 95% identical to SEQ ID NO: 79, and (ii) an ionizable lipid, wherein the ionizable lipid is Compound 18, a salt or a stereoisomer thereof, or any combination thereof, wherein the lipid nanoparticle comprises about 45 mol % to about 55 mol % of Compound 18.

9. The lipid nanoparticle of claim 8 , comprising from about 1 mol % to about 20 mol % of phospholipid.

10. The lipid nanoparticle of claim 8 , comprising from about 35 mol % to about 40 mol % of structural lipid.

11. The lipid nanoparticle of claim 8 , comprising from about 2 mol % to about 4 mol % of PEG lipid.

12. The lipid nanoparticle of claim 1 , wherein the mRNA comprises the nucleotide sequence of SEQ ID NO: 79.

13. The lipid nanoparticle of claim 1 , wherein the mRNA comprises a modified nucleotide.

14. The lipid nanoparticle of claim 1 , wherein (i) at least 95% of uridines in the ORF are 5-methoxyuridines, (ii) at least 99% of uridines in the ORF are 5-methoxyuridines, or (iii) 100% of uridines in the ORF are 5-methoxyuridines.

15. The lipid nanoparticle of claim 8 , wherein the mRNA comprises the nucleotide sequence of SEQ ID NO: 79.

16. The lipid nanoparticle of claim 8 , wherein the mRNA comprises a modified nucleotide.

17. The lipid nanoparticle of claim 8 , wherein (i) at least 95% of uridines in the ORF are 5-methoxyuridines, (ii) at least 99% of uridines in the ORF are 5-methoxyuridines, or (iii) 100% of uridines in the ORF are 5-methoxyuridines.

18. A lipid nanoparticle, comprising (i) an mRNA comprising an ORF encoding a human GLA polypeptide, wherein the mRNA comprises a nucleotide sequence at least 95% identical to SEQ ID NO: 79, (ii) an ionizable lipid, wherein the ionizable lipid is Compound 18, a salt or a stereoisomer thereof, or any combination thereof, (iii) a phospholipid, (iv) a PEG-lipid, and (v) a structural lipid.

19. The lipid nanoparticle of claim 18 , wherein the mRNA comprises the nucleotide sequence of SEQ ID NO: 79.

20. The lipid nanoparticle of claim 18 , wherein the mRNA comprises a modified nucleotide.

21. The lipid nanoparticle of claim 18 , wherein (i) at least 95% of uridines in the ORF are 5-methoxyuridines, (ii) at least 99% of uridines in the ORF are 5-methoxyuridines, or (iii) 100% of uridines in the ORF are 5-methoxyuridines.

Assignments (2)
SECURITY INTEREST Recorded Nov 19, 2025
From: MODERNATX, INC.
To: ARES CAPITAL CORPORATION, AS AGENT
Reel/Frame 073634/0354 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2020
From: MARTINI, PAOLO; HOGE, STEPHEN; BENENATO, KERRY; PRESNYAK, VLADIMIR; MCFAYDEN, IAIN; KUMARASINGHE, ELLALAHEWAGE SATHYAJITH; ZHU, XULING; GUEY, LIN TUNG; SABNIS, STACI
To: MODERNATX, INC.
Reel/Frame 051689/0038 →
Continuity (4)
Continuation 16110833 · Aug 23, 2018
Continuation PCTUS2017033398 · May 18, 2017
Provisional Application 62338354 · May 18, 2016
Related Publication 20200149052A1 · May 14, 2020