Polynucleotides encoding JAGGED1 for the treatment of Alagille syndrome

Patent metadata

Field	Value
Publication number	US-12128113-B2
Application number	US-201716302607-A
Country	US
Kind code	B2
Filing date	May 18, 2017
Priority date	May 18, 2016
Publication date	Oct 29, 2024
Grant date	Oct 29, 2024

Abstract

The invention relates to mRNA therapy for the treatment of Alagille syndrome (ALGS), mRNAs for use in the invention, when administered in vivo, encode JAGGED 1 (JAG1), isoforms thereof functional fragments thereof, and fusion proteins comprising JAG1, 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 JAG1 expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient JAG1 activity in subjects.

First claim

What is claimed is:

1. A composition comprising:
a lipid nanoparticle and
a messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding a human Jagged1 (JAG1) polypeptide,
wherein the lipid nanoparticle comprises an ionizable lipid, and
wherein the ionizable lipid comprises a compound of Formula (IIa), (IIc), or (IIe):

or a salt or stereoisomer thereof, wherein
R 4 is unsubstituted C 1-3 alkyl, or —(CH 2 ) n Q, in which n is 1, 2, 3, 4 or 5 and Q is OH, —NHC(S)N(R) 2 , or —NHC(O)N(R) 2 ; and
each R is independently selected from the group consisting of C 1-3 alkyl, C 2-3 alkenyl, and H.

2. The composition of claim 1 , wherein n is 2.

3. The composition of claim 1 , wherein the ionizable lipid comprises the compound of the formula:

or a salt thereof.

4. The composition of claim 1 , wherein the lipid nanoparticle further comprises a phospholipid, a structural lipid, and a PEG lipid.

5. The composition of claim 4 , wherein 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
mixtures thereof.

6. The composition of claim 1 , wherein the mRNA further comprises a microRNA (miRNA) binding site.

7. A pharmaceutical composition comprising a lipid nanoparticle and an mRNA comprising an ORF encoding a human JAG1 polypeptide, wherein the lipid nanoparticle comprises an ionizable lipid, and wherein the ionizable lipid comprises a compound selected from the group consisting of

or salts and stereoisomers thereof, and any combination thereof.

8. The composition of claim 4 , wherein the structural lipid is selected from the group consisting of: cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, and mixtures thereof.

9. The composition of claim 4 , wherein the PEG lipid is selected from the group consisting of: 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, and mixtures thereof.

10. The composition of claim 4 , wherein the PEG lipid is (Compound 428).

11. A composition comprising:
(a) a lipid nanoparticle; and
(b) a messenger ribonucleic acid (mRNA) comprising an open reading frame (ORF) encoding a human Jagged1 (JAG1) polypeptide,
wherein the lipid nanoparticle comprises
(i) the ionizable lipid of the formula

(ii) 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC),
(iii) cholesterol, and
(iv) a PEG lipid of the formula

12. The composition of claim 1 , wherein the ORF comprises at least one chemically modified nucleobase, sugar, backbone, or any combination thereof.

13. The composition of claim 12 , wherein the at least one chemically modified nucleobase is selected from the group consisting of pseudouracil (ψ), N1-methylpseudouracil (m1ψ), 1-ethylpseudouracil, 2-thiouracil (s2U), 4′-thiouracil, 5-methylcytosine, 5-methyluracil, 5-methoxyuracil, and any combination thereof.

14. The composition of claim 12 , wherein the at least one chemically modified nucleobase is N1-methylpseudouracil (m1ψ).

15. The composition of claim 3 , wherein the lipid nanoparticle further comprises a phospholipid, a structural lipid, and a PEG lipid.

16. The composition of claim 15 , wherein 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
mixtures thereof.

17. The composition of claim 3 , wherein the mRNA further comprises a microRNA (miRNA) binding site.

18. The composition of claim 15 , wherein the structural lipid is selected from the group consisting of: cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocophe

Assignees

• Modernatx Inc

Inventors

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

Classifications

• A61K9/5123

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

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title

• C07K14/705

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• A61K47/28

  Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid · CPC title

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title