Polynucleotides encoding porphobilinogen deaminase for the treatment of acute intermittent porphyria

Patent metadata

Field	Value
Publication number	US-12377136-B2
Application number	US-202217813984-A
Country	US
Kind code	B2
Filing date	Jul 21, 2022
Priority date	May 18, 2016
Publication date	Aug 5, 2025
Grant date	Aug 5, 2025

Abstract

The invention relates to mRNA therapy for the treatment of Acute Intermittent Porphyria (AIP). mRNAs for use in the invention, when administered in vivo, encode human porphobilinogen deaminase (PBGD), isoforms thereof, functional fragments thereof, and fusion proteins comprising PBGD. mRNAs of the invention are preferably encapsulated in lipid nanoparticles (LNPs) to affect efficient delivery to cells and/or tissues in subjects, when administered thereto. mRNA therapies of the invention increase and/or restore deficient levels of PBGD expression and/or activity in subjects. mRNA therapies of the invention further decrease levels of toxic metabolites associated with deficient PBGD activity in subjects, namely porphobilinogen and aminolevulinate (PBG and ALA).

First claim

What is claimed is:

1. A method of treating an acute Porphyria attack in a human subject in need thereof, the method comprising administering to the human subject a lipid nanoparticle comprising a therapeutically effective amount of a messenger RNA (mRNA) encoding a porphobilinogen deaminase (PBGD) polypeptide, wherein the mRNA comprises an open reading frame comprising the nucleotide sequence set forth in SEQ ID NO: 102 or SEQ ID NO: 104, and wherein the human subject has acute intermittent Porphyria.

2. The method of claim 1 , wherein the mRNA comprises at least one chemically modified nucleobase.

3. The method of claim 2 , wherein the at least one chemically modified nucleobase is selected from the group consisting of pseudouracil, N1-methylpseudouracil, 1-ethylpseudouracil, 2-thiouracil, 4′-thiouracil, 5-methylcytosine, 5-methyluracil, 5-methoxyuracil, and any combination thereof.

4. The method of claim 3 , wherein the at least one chemically modified nucleobase is 5-methoxyuracil.

5. The method of claim 4 , wherein at least 95% of uracil in the mRNA is 5-methoxyuracil.

6. The method of claim 4 , wherein 100% of uracil in the mRNA is 5-methoxyuracil.

7. The method of claim 3 , wherein the at least one chemically modified nucleobase is N1-methylpseudouracil.

8. The method of claim 1 , wherein the lipid nanoparticle is administered intravenously.

9. The method of claim 1 , wherein the lipid nanoparticle is administered to the human subject about once every two weeks.

10. The method of claim 1 , wherein the open reading frame comprises the nucleotide sequence set forth in SEQ ID NO: 102.

11. The method of claim 1 , wherein the open reading frame comprises the nucleotide sequence set forth in SEQ ID NO: 104.

Assignees

• Modernatx Inc
• Fundacion Para La Investig Medica Aplicada

Inventors

• Martini Paolo
• Hoge Stephen
• Benenato Kerry
• Presnyak Vladimir
• Jiang Lei
• Mcfadyen Iain
• Kumarasinghe Ellalahewage Sathyajith
• Fontanellas Roma Antonio
• Berraondo Lopez Pedro
• Avila Zaragoza Matias Antonio
• Guey Lin Tung
• Sabnis Staci

Classifications

• C12N15/88

  using microencapsulation, e.g. using {amphiphile} liposome vesicle · CPC title

• A61P7/08

  Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04) · CPC title

• A61K48/0033

  the non-active part being non-polymeric · CPC title

• A61K48/005

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

• C12Y205/01061

  Hydroxymethylbilane synthase (2.5.1.61) · CPC title