IP Library › Granted Patent US 12685785

Granted Patent B2

US 12685785 · App. 18/327,728 · Granted Jul 21, 2026

Polynucleotides encoding propionyl-CoA carboxylase alpha and beta subunits for the treatment of propionic acidemia

Inventors: Lei Jiang (Cambridge, MA); Lin Tung Guey (Lexington, MA); Paolo G. V. Martini (Boston, MA); Vladimir Presnyak (Manchester, NH)

Assignee: ModernaTX, Inc.

A61K48/0033 A61K9/1271 A61K38/53 A61P3/00 C12Y604/01003

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Quick Facts

Patent No.: US 12685785
App. No.: 18/327,728
Filed: Jun 1, 2023
Granted: Jul 21, 2026
Kind: B2
Examiner: POPA, ILEANA
Art Unit: 1633
USPC: 514/44R

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

This disclosure relates to mRNA therapy for the treatment of propionic acidemia (PA). mRNAs for use in the invention, when administered in vivo, encode human propionyl-CoA carboxylase alpha (PCCA) and/or human propionyl-CoA carboxylase beta (PCCB), and isoforms thereof, functional fragments thereof, and fusion proteins comprising PCCA and/or PCCB. 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 propionyl-CoA carboxylase (PCC) expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of disease-associated toxic metabolites associated with deficient PCCA or PCCB activity, in subjects.

Claims (53)

1 . A messenger RNA (mRNA) comprising:

(i) a 5′-terminal cap;

(ii) a 5′ untranslated region (UTR);

(iii) an open reading frame (ORF) encoding the propionyl-CoA carboxylase alpha (PCCA) polypeptide set forth in SEQ ID NO:1, wherein the ORF has at least 93% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:11;

(iv) a 3′ UTR; and

(v) a poly-A-region.

2 . The mRNA of claim 1 , wherein the ORF has at least 95% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:11.

3 . The mRNA of claim 1 , wherein the ORF has at least 98% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:11.

4 . The mRNA of claim 1 , wherein the ORF has at least 99% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:11.

5 . The mRNA of claim 1 , wherein the ORF has the nucleic acid sequence set forth in SEQ ID NO: 11.

6 . The mRNA of claim 1 , wherein the 5′ UTR comprises the nucleic acid sequence set forth in SEQ ID NO:199.

7 . The mRNA of claim 1 , wherein the 3′ UTR comprises the nucleic acid sequence set forth in SEQ ID NO:178.

8 . The mRNA of claim 1 , wherein the 5′ UTR comprises the nucleic acid sequence set forth in SEQ ID NO:199, and wherein the 3′ UTR comprises the nucleic acid sequence set forth in SEQ ID NO:178.

9 . The mRNA of claim 1 , comprising the nucleic acid sequence set forth in SEQ ID NO:203.

10 . The mRNA of claim 1 , wherein the poly-A region is at least 100 nucleotides in length.

11 . The mRNA of claim 1 , wherein all of the uracils are N1-methylpseudouracils.

12 . The mRNA of claim 5 , wherein the poly-A region is at least 100 nucleotides in length.

13 . The mRNA of claim 5 , wherein all of the uracils are N1-methylpseudouracils.

14 . The mRNA of claim 9 , wherein the poly-A region is at least 100 nucleotides in length.

15 . The mRNA of claim 9 , wherein all of the uracils are N1-methylpseudouracils.

16 . The mRNA of claim 14 , wherein all of the uracils are N1-methylpseudouracils.

17 . A pharmaceutical composition comprising a first mRNA and a second mRNA,

wherein the first mRNA comprises (i) a first 5′-terminal cap, (ii) a first 5′ UTR, (iii) a first ORF encoding the PCCA polypeptide set forth in SEQ ID NO:1, wherein the ORF has at least 93% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:11, (iv) a first 3′ UTR, and (v) a first poly-A-region, and

wherein the second mRNA comprises (i) a second 5′-terminal cap, (ii) a second 5′ UTR, (iii) a second ORF encoding the PCCB polypeptide set forth in SEQ ID NO:15, wherein the ORF has at least 93% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:25, (iv) a second 3′ UTR, and (v) a second poly-A-region.

18 . The pharmaceutical composition of claim 17 , wherein the first ORF has at least 95% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 11, and wherein the second ORF has at least 95% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:25.

19 . The pharmaceutical composition of claim 17 , wherein the first ORF has at least 98% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 11, and wherein the second ORF has at least 98% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:25.

20 . The pharmaceutical composition of claim 17 , wherein the first ORF has at least 99% sequence identity to the nucleic acid sequence set forth in SEQ ID NO: 11, and wherein the second ORF has at least 99% sequence identity to the nucleic acid sequence set forth in SEQ ID NO:25.

21 . The pharmaceutical composition of claim 17 , wherein the first ORF has to the nucleic acid sequence set forth in SEQ ID NO:11, and wherein the second ORF has the nucleic acid sequence set forth in SEQ ID NO:25.

22 . The pharmaceutical composition of claim 17 , wherein the first 5′ UTR comprises the nucleic acid sequence set forth in SEQ ID NO: 199, wherein the first 3′ UTR comprises the nucleic acid sequence set forth in SEQ ID NO:178, wherein the second 5′ UTR comprises the nucleic acid sequence set forth in SEQ ID NO: 199, and wherein the second 3′ UTR comprises the nucleic acid sequence set forth in SEQ ID NO:178.

23 . The pharmaceutical composition of claim 17 , wherein the first mRNA comprises the nucleic acid sequence set forth in SEQ ID NO:203, and wherein the second mRNA comprises the nucleic acid sequence set forth in SEQ ID NO:205.

24 . The pharmaceutical composition of claim 17 , wherein the first poly-A region is at least 100 nucleotides in length, and wherein the second poly-A region is at least 100 nucleotides in length.

25 . The pharmaceutical composition of claim 17 , wherein all of the uracils of the first mRNA are N1-methylpseudouracils, and wherein all of the uracils of the second mRNA are N1-methylpseudouracils.

26 . The pharmaceutical composition of claim 21 , wherein the first poly-A region is at least 100 nucleotides in length, and wherein the second poly-A region is at least 100 nucleotides in length.

27 . The pharmaceutical composition of claim 21 , wherein all of the uracils of the first mRNA are N1-methylpseudouracils, and wherein all of the uracils of the second mRNA are N1-methylpseudouracils.

28 . The pharmaceutical composition of claim 23 , wherein the first poly-A region is at least 100 nucleotides in length, and wherein the second poly-A region is at least 100 nucleotides in length.

29 . The pharmaceutical composition of claim 23 , wherein all of the uracils of the first mRNA are N1-methylpseudouracils, and wherein all of the uracils of the second mRNA are N1-methylpseudouracils.

30 . The pharmaceutical composition of claim 28 , wherein all of the uracils of the first mRNA are N1-methylpseudouracils, and wherein all of the uracils of the second mRNA are N1-methylpseudouracils.

31 . The pharmaceutical composition of claim 17 , wherein the first mRNA and the second mRNA are encapsulated into a lipid nanoparticle.

32 . The pharmaceutical composition of claim 31 , wherein the lipid nanoparticle comprises an ionizable lipid, a structural lipid, a phospholipid, and a polyethylene glycol (PEG)-modified lipid.

33 . The pharmaceutical composition of claim 32 , wherein the ionizable lipid is

or a salt thereof, wherein the structural lipid is cholesterol, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and wherein the PEG-modified lipid is 1,2-dimyristoyl-sn-glycerol methoxypolyethylene glycol (PEG-DMG) or Compound I

34 . The pharmaceutical composition of claim 21 , wherein the first mRNA and the second mRNA are encapsulated into a lipid nanoparticle.

35 . The pharmaceutical composition of claim 34 , wherein the lipid nanoparticle comprises an ionizable lipid, a structural lipid, a phospholipid, and a polyethylene glycol (PEG)-modified lipid.

36 . The pharmaceutical composition of claim 35 , wherein the ionizable lipid is

37 . The pharmaceutical composition of claim 25 , wherein the first mRNA and the second mRNA are encapsulated into a lipid nanoparticle.

38 . The pharmaceutical composition of claim 37 , wherein the lipid nanoparticle comprises an ionizable lipid, a structural lipid, a phospholipid, and a polyethylene glycol (PEG)-modified lipid.

39 . The pharmaceutical composition of claim 38 , wherein the ionizable lipid is

40 . The pharmaceutical composition of claim 27 , wherein the first mRNA and the second mRNA are encapsulated into a lipid nanoparticle.

41 . The pharmaceutical composition of claim 40 , wherein the lipid nanoparticle comprises an ionizable lipid, a structural lipid, a phospholipid, and a polyethylene glycol (PEG)-modified lipid.

42 . The pharmaceutical composition of claim 41 , wherein the ionizable lipid is