IP Library › Granted Patent US 12,644,102
Granted Patent B2
US 12,644,102 · App. 17/275,082 · Granted Jun 2, 2026

Polynucleotides encoding branched-chain alpha-ketoacid dehydrogenase complex E1-α, E1-β, and E2 subunits for the treatment of maple syrup urine disease

Inventors: Paolo G. V. Martini (Boston, MA); Vladimir Presnyak (Manchester, NH); Paloma Hoban Giangrande (Belmont, MA); Kimberly Ann Coughlan (Watertown, MA)
Assignee: ModernaTX, Inc.
C12N9/0008A61K9/5123A61P3/00C12N9/0051C12N9/1029C12N15/88C12Y102/04004C12Y108/01004C12Y203/01012A61K48/00
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Quick Facts
Patent No.
US 12,644,102
App. No.
17/275,082
Granted
Jun 2, 2026
Kind
B2
Abstract

This disclosure relates to mRNA therapy for the treatment of maple syrup urine disease (MSUD). mRNAs for use in the invention, when administered in vivo, encode branched chain α-ketoacid dehydrogenase complex (BCKDC) E1α, E1β, or E2mRNA therapies of the disclosure increase and/or restore deficient levels of E1α, E1β, or E2 expression and/or BCKDC activity in subjects. mRNA therapies of the invention further decrease abnormal accumulation of branched chain amino acids associated with deficient BCKDC activity in subjects.

Claims (14)

1 . A pharmaceutical composition comprising a lipid nanoparticle, a first mRNA, a second mRNA, and a third mRNA, wherein the first mRNA comprises a first open reading frame (ORF) encoding a branched-chain α-ketoacid dehydrogenase complex (BCKDC) Ela polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 1 or 19, wherein the second mRNA comprises a second ORF encoding a BCKDC E1β polypeptide comprising the amino acid sequence set forth in SEQ ID NO:9, wherein the third mRNA comprises a third ORF encoding a BCKDC E2 polypeptide comprising the amino acid sequence set forth in SEQ ID NO:14, and wherein all of the uracils in the first mRNA, the second mRNA, and the third mRNA are N1-methylpseudouracils.

2 . The pharmaceutical composition of claim 1 , wherein the lipid nanoparticle comprises:

(i)

 (ii) cholesterol, and (iii) PEG-DMG or

(i) Compound II, (ii) 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), (iii) cholesterol, and (iv) PEG-DMG or Compound I;

(i) Compound II, (ii) cholesterol, and (iii) Compound I; or

(i) Compound II, (ii) DSPC or DOPE, (iii) cholesterol, and (iv) Compound I.

3 . A method of expressing a branched-chain α-ketoacid dehydrogenase complex (BCKDC) Ela polypeptide, Elβ polypeptide, and E2 polypeptide in a human subject in need thereof, comprising administering intravenously to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1 .

4 . A method of treating maple syrup urine disease (MSUD) in a human subject in need thereof, comprising administering intravenously to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1 .

5 . The method of claim 4 , wherein the administration to the subject is about once a week or about once every two weeks.

6 . A method of reducing leucine, isoleucine, and/or valine blood levels in a human subject in need thereof, comprising administering intravenously to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1 .

7 . A method of reducing leucine, isoleucine, and/or valine urine level in a human subject in need thereof, comprising administering intravenously to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1 .

8 . A method of increasing branched chain α-ketoacid dehydrogenase complex (BCKDC) activity in a human subject in need thereof, comprising administering intravenously to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1 .

9 . The method of claim 8 , wherein the BCKDC activity is increased in the liver of the subject.

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 May 10, 2021
From: MARTINI, PAOLO; PRESNYAK, VLADIMIR; GIANGRANDE, PALOMA HOBAN; COUGHLAN, KIMBERLY ANN
To: MODERNATX, INC.
Reel/Frame 056188/0527 →
Continuity (3)
Provisional Application 62755060 · Nov 2, 2018
Provisional Application 62730968 · Sep 13, 2018
Related Publication 20220243182A1 · Aug 4, 2022
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