Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis

Patent metadata

Field	Value
Publication number	US-11801227-B2
Application number	US-201716302370-A
Country	US
Kind code	B2
Filing date	May 18, 2017
Priority date	May 18, 2016
Publication date	Oct 31, 2023
Grant date	Oct 31, 2023

Abstract

The invention relates to mRNA therapy for the treatment of cystic fibrosis. mRNAs for use in the invention, when administered in vivo, encode cystic fibrosis transmembrane conductance regulator (CFTR), isoforms thereof, functional fragments thereof, and fusion proteins comprising CFTR. 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 CFTR expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient CFTR activity in subjects.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a lipid nanoparticle, wherein the lipid nanoparticle comprises a compound selected from the group consisting of

or salts and stereoisomers thereof,
wherein the lipid nanoparticle comprises an mRNA that comprises an open reading frame (ORF) encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide.

2. The pharmaceutical composition of claim 1 , wherein the lipid nanoparticle further comprises a phospholipid.

3. The pharmaceutical composition of claim 1 , wherein the lipid nanoparticle further comprises a structural lipid.

4. The pharmaceutical composition of claim 1 , wherein the lipid nanoparticle further comprises a polyethylene glycol lipid.

5. The pharmaceutical composition of claim 1 , wherein the lipid nanoparticle further comprises a phospholipid, a structural lipid, and a polyethylene glycol lipid.

6. The pharmaceutical composition of claim 2 , 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), and sphingomyelin.

7. The pharmaceutical composition of claim 3 , wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, and alpha-tocopherol.

8. The pharmaceutical composition of claim 4 , wherein the polyethylene glycol lipid is selected from the group consisting of a polyethylene glycol-modified phosphatidylethanolamine, a polyethylene glycol-modified phosphatidic acid, a polyethylene glycol-modified ceramide, a polyethylene glycol-modified dialkylamine, a polyethylene glycol-modified diacylglycerol, and a polyethylene glycol-modified dialkylglycerol.

9. The pharmaceutical composition of claim 5 , 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), and sphingomyelin;
(ii) the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, and alpha-tocopherol; and
(iii) the polyethylene glycol lipid is selected from the group consisting of a polyethylene glycol-modified phosphatidylethanolamine, a polyethylene glycol-modified phosphatidic acid, a polyethylene glycol-modified ceramide, a polyethylene glycol-modified dialkylamine, a polyethylene glycol-modified diacylglycerol, and a polyethylene glycol-modified dialkylglycerol.

10. A method of expressing a CFTR polypeptide in a human subject that has cystic fibrosis comprising administering to the human subject an effective amount of the pharmaceutical composition of claim 1 .

11. A method of treating cystic fibrosis in a human subject in need thereof, comprising administering to the human subject an effective amount of the pharmaceutical composition of claim 1 .

12. A method of improving the measure of at least one respiratory volume in a human subject that has cystic fibrosis, comprising administering to the human subject an effective amount of the pharmaceutical composition of claim 1 .

13. The method of claim 12 , wherein the at least one respiratory volume is selected from the group consisting of tidal volume, inspiratory reserve volume, expiratory reserve volume, residual volume, vital capacity, and total lung capacity.

14. A method of reducing sweat gland secretion of chloride in a human subject that has cystic fibrosis, comprising administering to the human subject an effective amount of the pharmaceutical composition of claim 1 .

15. A method of increasing the pH of airway secretions in a human subject that has cystic fibrosis, comprising administering to the human subject an effective amount of the pharmaceutical composition of claim 1 .

16. A pharmaceutical composition comprising a lipid nanoparticle, wherein the lipid nanoparticle comprises Compound 18,

or a salt thereof,
wherein the lipid nanoparticle comprises an mRNA that comprises an open reading frame (ORF) encoding a cystic fibrosis transmembrane conductance regulator (CFTR) polypeptide.

17. The pharmaceutical composition of claim 16 , wherein the lipid nanoparticle further comprises a phospholipid.

18. The pharmaceutical composition of claim 16 ,

Assignees

• Modernatx Inc

Inventors

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

Classifications

• A61K9/5123 Primary

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

• A61K9/0043

  Nose · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title

• A61K9/0073

  Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M) · CPC title

• A61K38/177

  Receptors; Cell surface antigens; Cell surface determinants · CPC title