Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria

Patent metadata

Field	Value
Publication number	US-11939601-B2
Application number	US-201816765656-A
Country	US
Kind code	B2
Filing date	Nov 21, 2018
Priority date	Nov 22, 2017
Publication date	Mar 26, 2024
Grant date	Mar 26, 2024

Abstract

This disclosure relates to mRNA therapy for the treatment of hyperphenylalaninemias such as phenylketonuria (PKU). mRNAs for use in the invention, when administered in vivo, encode human phenylalanine hydroxylase (PAH), functional fragments thereof (e.g., those comprising the catalytic domain or the catalytic domain and the tetramerization domains), and fusion proteins comprising PAH. 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 PAH expression and/or activity in subjects. mRNA therapies of the invention further decrease abnormal accumulation of phenylalanine associated with deficient PAH activity in subjects.

First claim

What is claimed is:

1. A method of treating phenylketonuria in a human subject that has phenylketonuria, comprising administering to the human subject an effective amount of a pharmaceutical composition comprising a lipid nanoparticle comprising

or a salt thereof, wherein the pharmaceutical composition comprises an mRNA comprising an open reading frame encoding a phenylalanine hydroxylase polypeptide.

2. The method of claim 1 , wherein the lipid nanoparticle further comprises a phospholipid, a structural lipid, and a PEG-modified lipid.

3. The method of claim 1 , wherein the administration to the human subject is about once a week, about once every two weeks, or about once a month.

4. The method of claim 1 , wherein the pharmaceutical composition is administered intravenously.

5. The method of claim 1 , wherein the pharmaceutical composition is administered subcutaneously.

6. The method of claim 2 , wherein the phospholipid is 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), wherein the structural lipid is cholesterol, and wherein the PEG-modified lipid is PEG-DMG or

7. The method of claim 2 , wherein the phospholipid is DSPC, wherein the structural lipid is cholesterol, and wherein the PEG-modified lipid is Compound I.

8. The method of claim 6 , wherein the administration to the human subject is about once a week, about once every two weeks, or about once a month.

9. The method of claim 6 , wherein the pharmaceutical composition is administered intravenously.

10. The method of claim 6 , wherein the pharmaceutical composition is administered subcutaneously.

11. The method of claim 3 , wherein the pharmaceutical composition is administered intravenously.

12. The method of claim 3 , wherein the pharmaceutical composition is administered subcutaneously.

13. The method of claim 8 , wherein the pharmaceutical composition is administered intravenously.

14. The method of claim 8 , wherein the pharmaceutical composition is administered subcutaneously.

15. The method of claim 7 , wherein the administration to the human subject is about once a week, about once every two weeks, or about once a month.

16. The method of claim 7 , wherein the pharmaceutical composition is administered intravenously.

17. The method of claim 7 , wherein the pharmaceutical composition is administered subcutaneously.

18. The method of claim 15 , wherein the pharmaceutical composition is administered intravenously.

19. The method of claim 15 , wherein the pharmaceutical composition is administered subcutaneously.

Assignees

• Modernatx Inc

Inventors

• Rajendran Raj
• Finn Patrick
• Martini Paolo G V
• An Ding
• Dousis Athanasios
• Ravichandran Kanchana

Classifications

• C12N9/0071 Primary

  acting on paired donors with incorporation of molecular oxygen (1.14) · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title

• A61K9/5123

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

• A61K48/0075

  characterised by an aspect of the delivery route, e.g. oral, subcutaneous · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title