Polynucleotides encoding methylmalonyl-CoA mutase

Patent metadata

Field	Value
Publication number	US-11504337-B2
Application number	US-201916515256-A
Country	US
Kind code	B2
Filing date	Jul 18, 2019
Priority date	Dec 17, 2015
Publication date	Nov 22, 2022
Grant date	Nov 22, 2022

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.

First claim

The invention claimed is:

1. A lipid nanoparticle composition comprising:
a messenger RNA (mRNA) that comprises an open reading frame (ORF) encoding a methylmalonyl-CoA mutase (MCM) polypeptide, and
a compound of Formula (IA):

or a salt or stereoisomer thereof, wherein:
l is selected from 1, 2, 3, 4, and 5;
m is selected from 5, 6, 7, 8, and 9;
M 1 is a bond or M′;
R 4 is unsubstituted C 1-3 alkyl, or —(CH 2 ) n Q, wherein n is 1, 2, 3, 4 or 5 and Q is OH, —NHC(S)N(R) 2 , or —NHC(O)N(R) 2 ;
M and M′ are independently selected from —C(O)O, OC(O), C(O)N(R′), P(O)(OR′)O, an aryl group, and a heteroaryl group;
R 2 and R 3 are independently selected from the group consisting of H, C 1-14 alkyl, and C 2-14 alkenyl;
each R is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H;
each R′ is independently selected from the group consisting of C 1-18 alkyl, C 2-18 alkenyl, —R*YR″, —YR″, and H;
each R″ is independently selected from the group consisting of C 3-14 alkyl and C 3-14 alkenyl;
each R* is independently selected from the group consisting of C 1-12 alkyl and C 2-12 alkenyl; and
each Y is independently a C 3-6 carbocycle.

2. The lipid nanoparticle composition of claim 1 , wherein the compound is a compound of Formula (II):

or a salt or stereoisomer thereof, wherein:
R 4 is unsubstituted C 1-3 alkyl, or —(CH 2 ) n Q, wherein n is 2, 3, or 4 and Q is OH, —NHC(S)N(R) 2 , or —NHC(O)N(R) 2 .

3. The lipid nanoparticle composition of claim 1 , wherein the compound is a compound of Formula (IIa), (IIb), (IIc), or (IIe):

or a salt or stereoisomer thereof.

4. The lipid nanoparticle composition of claim 1 , wherein M and M′ are independently —C(O)O— or —OC(O)—.

5. The lipid nanoparticle composition of claim 1 , wherein R 2 and R 3 are the same.

6. The lipid nanoparticle composition of claim 1 , wherein R 2 and R 3 are C 8 alkyl.

7. The lipid nanoparticle composition of claim 1 , wherein R 2 and R 3 are different.

8. The lipid nanoparticle composition of claim 1 , wherein n is 2.

9. The lipid nanoparticle composition of claim 1 , wherein R′ is selected from: C 4 alkyl, C 4 alkenyl, C 5 alkyl, C 5 alkenyl, C 6 alkyl, C 6 alkenyl, C 7 alkyl, C 7 alkenyl, C 9 alkyl, C 9 alkenyl, C 11 alkyl, C 11 alkenyl, C 12 alkyl, C 12 alkenyl, C 13 alkyl, C 13 alkenyl, C 14 alkyl, C 14 alkenyl, C 15 alkyl, C 15 alkenyl, C 16 alkyl, C 16 alkenyl, C 17 alkyl, C 17 alkenyl, C 18 alkyl, and C 18 alkenyl.

10. The lipid nanoparticle composition of claim 1 , wherein l is selected from 3, 4, and 5.

11. The lipid nanoparticle composition of claim 1 , wherein:
(i) n is 2;
(ii) R′ is selected from: C 4 alkyl, C 4 alkenyl, C 5 alkyl, C 5 alkenyl, C 6 alkyl, C 6 alkenyl, C 7 alkyl, C 7 alkenyl, C 9 alkyl, C 9 alkenyl, C 11 alkyl, C 11 alkenyl, C 12 alkyl, C 12 alkenyl, C 13 alkyl, C 13 alkenyl, C 14 alkyl, C 14 alkenyl, C 15 alkyl, C 15 alkenyl, C 16 alkyl, C 16 alkenyl, C 17 alkyl, C 17 alkenyl, C 18 alkyl, and C 18 alkenyl; and
(iii) l is selected from 3, 4, and 5.

12. The lipid nanoparticle composition of claim 1 , wherein the compound is a compound of formula:

or a salt thereof.

13. The lipid nanoparticle composition of claim 1 , further comprising a phospholipid, a structural lipid, and a PEG lipid.

14. The lipid nanoparticle composition of claim 13 , wherein:
(i) the phospholipid is selected from the group consisting of:
1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC),
1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC),
1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC),
1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC),
1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC),
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC),
1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC),
1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC),
1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC),
1,2-dilinolenoyl-sn-glycero-3-phosphocholine,
1,2-diarachidonoyl-sn-glycero-3-phosphocholine,
1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine,
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE),
1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16:0 PE),
1,2-distearoyl-sn-glycero-3-phosphoethanolamine,
1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine,
1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine,
1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine,
1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine,
1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG),
sphingomyelin, and
any mixtures thereof;
(ii) the structural lipid is cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, or any mixture thereof; and
(iii) the PEG lipid is a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, or any mixture thereof.

15. The lipid nanoparticle composition of claim 13 , wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and the structural lipid is cholesterol.

16. The lipid nanoparticle composition of claim 1 , wherein the ORF encodes the human MCM polypeptide of SEQ ID NO:208, SEQ ID NO:209, SEQ ID NO:210, SEQ ID NO:211, SEQ ID NO:212, or SEQ ID NO:213.

17. The lipid nanoparticle composition of claim 1 , wherein the ORF encodes the human MCM polypeptide of SEQ ID NO:213.

18. The lipid nanoparticle composition of claim 1 , wherein the ORF encodes the human MCM polypeptide of SEQ ID NO:208.

19. The lipid nanoparticle composition of claim 12 , wherein the ORF encodes the human MCM polypeptide of SEQ ID NO:213.

Assignees

• Modernatx Inc

Inventors

• Martini Paolo
• Presnyak Vladimir
• Benenato Kerry
• Hoge Stephen
• Mcfadyen Iain
• Kumarasinghe Ellalahewage Sathyajith

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K38/00 Primary

  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 title

• A61K48/005

  characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered · CPC title

• C12Y504/99002

  Methylmalonyl-CoA mutase (5.4.99.2) · CPC title

• A61K9/5123 Primary

  Organic compounds, e.g. fats, sugars · CPC title