POLYNUCLEOTIDES ENCODING METHYLMALONYL-CoA MUTASE

• US 20180271795A1
• Filed: 06/07/2018
• Published: 09/27/2018
• Est. Priority Date: 12/17/2015
• Status: Active Grant

• Current Assignee: Moderna TX, Inc. (Moderna, Inc.)
• Original Assignee: Moderna TX, Inc. (Moderna, Inc.)
• Inventors: Martini, Paolo, Presnyak, Vladimir
• Granted Patent: US 10,406,112 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/52 Isomerases (5)
• CPC Class Codes: A61K 48/005 characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/52 Genes encoding for enzymes or proenzymes
• CPC Class Codes: C12N 9/90 Isomerases (5.)
• CPC Class Codes: C12Y 504/99002 Methylmalonyl-CoA mutase (5.4.99.2)

Abstract

The disclosure relates to polynucleotides comprising an open reading frame of linked nucleosides encoding human methylmalonyl-CoA mutase precursor, human methylmalonyl-CoA mutase (MCM) mature form, or functional fragments thereof. In some embodiments, the disclosure includes methods of treating methylmalonic acidemia in a subject in need thereof comprising administering an mRNA encoding an MCM polypeptide.

Claims

1-15. -15. (canceled)

16. A lipid nanoparticle comprising a messenger RNA (mRNA) and a compound having the formula:

17. The lipid nanoparticle of claim 16, wherein the ORF encodes the human MCM polypeptide of SEQ ID NO:

213.

18. The lipid nanoparticle of claim 17, wherein the ORF is at least 80% identical to the nucleotide sequence of SEQ ID NO:

732.

19. The lipid nanoparticle of claim 17, wherein the ORF is at least 85% identical to the nucleotide sequence of SEQ ID NO:

732.

20. The lipid nanoparticle of claim 17, wherein the ORF is at least 90% identical to the nucleotide sequence of SEQ ID NO:

732.

21. The lipid nanoparticle of claim 17, wherein the ORF is at least 95% identical to the nucleotide sequence of SEQ ID NO:

732.

22. The lipid nanoparticle of claim 17, wherein the ORF is at least 98% identical to the nucleotide sequence of SEQ ID NO:

732.

23. The lipid nanoparticle of claim 17, wherein the ORF is at least 99% identical to the nucleotide sequence of SEQ ID NO:

732.

24. The lipid nanoparticle of claim 17, wherein the ORF is 100% identical to the nucleotide sequence of SEQ ID NO:

732.

25. The lipid nanoparticle of claim 18, wherein the 5′

UTR comprises the nucleotide sequence of SEQ ID NO;

215.

26. The lipid nanoparticle of claim 18, wherein the mRNA comprises the miR-142-3p binding site depicted in SEQ ID NO:

722.

27. The lipid nanoparticle of claim 18, wherein the 5′

terminal cap is Cap1.

28. The lipid nanoparticle of claim 18, wherein the poly-A tail is 100 residues in length.

29. The lipid nanoparticle of claim 18, wherein at least 95% of uridines in the mRNA are 5-methoxyuridines.

30. The lipid nanoparticle of claim 24, wherein the 5′

UTR comprises the nucleotide sequence of SEQ ID NO;

215.

31. The lipid nanoparticle of claim 24, wherein the mRNA comprises the miR-142-3p binding site depicted in SEQ ID NO:

722.

32. The lipid nanoparticle of claim 24, wherein the 5′

terminal cap is Cap1.

33. The lipid nanoparticle of claim 24, wherein the poly-A tail is 100 residues in length.

34. The lipid nanoparticle of claim 24, wherein at least 95% of uridines in the mRNA are 5-methoxyuridines.

35. The lipid nanoparticle of claim 24, wherein the 5′

UTR comprises the nucleotide sequence of SEQ ID NO;

215, wherein the mRNA comprises the miR-142-3p binding site depicted in SEQ ID NO;

722, wherein the 5′

terminal cap is Cap1, wherein the poly-A tail is 100 residues in length, and wherein at least 95% of uridines in the mRNA are 5-methoxyuridines.

36. The lipid nanoparticle of claim 16, further comprising a phospholipid, a structural lipid, and a PEG lipid.

37. The lipid nanoparticle of claim 24, further comprising a phospholipid, a structural lipid, and a PEG lipid.

38. The lipid nanoparticle of claim 35, further comprising a phospholipid, a structural lipid, and a PEG lipid.

39. The lipid nanoparticle of claim 36, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and the structural lipid is cholesterol.

40. The lipid nanoparticle of claim 37, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and the structural lipid is cholesterol.

41. The lipid nanoparticle of claim 38, wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and the structural lipid is cholesterol.

42. A method of treating methylmalonic acidemia in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the lipid nanoparticle of claim 16.

43. A method of treating methylmalonic acidemia in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the lipid nanoparticle of claim 17.

44. A method of treating methylmalonic acidemia in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the lipid nanoparticle of claim 24.

45. A method of treating methylmalonic acidemia in a human subject in need thereof, the method comprising administering to the human subject an effective amount of the lipid nanoparticle of claim 35.