IP Library › Granted Patent US 12,268,754
Granted Patent B2
US 12,268,754 · App. 17/448,996 · Granted Apr 8, 2025

Composition and methods for treatment of ornithine transcarbamylase deficiency

Inventors: Kim Askew (Lexington, MA); Jou-Ku Chung (Lexington, MA); Frank DeRosa (Lexington, MA); Michael Heartlein (Lexington, MA); Shrirang Karve (Lexington, MA); Thomas McCauley (Lexington, MA); Lianne Smith (Lexington, MA); Ann J. Barbier (Lexington, MA)
Assignee: TRANSLATE BIO, INC.
A61K48/005A61K9/0019A61K9/1272A61K38/45A61K47/6929A61K48/0025A61K48/0075A61K48/0083A61P3/00C12N15/52C12N15/85C12Y201/03003
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Quick Facts
Patent No.
US 12,268,754
App. No.
17/448,996
Granted
Apr 8, 2025
Kind
B2
Abstract

The present invention provides, among other things, methods of treating ornithine transcarbamylase deficiency, including administering to a subject in need of treatment a composition comprising an mRNA encoding an ornithine transcarbamylase protein at a low dose and at an administration interval such that at least one symptom or feature of the OTC deficiency is reduced.

Claims (19)

1. A method of treating ornithine transcarbamylase (OTC) deficiency in a human, comprising administering to a human in need of treatment a pharmaceutical composition comprising an mRNA encoding an ornithine transcarbamylase protein formulated in a lipid nanoparticle,

wherein the mRNA encoding the ornithine transcarbamylase protein is administered at a therapeutic low dose of 0.5 mg/kg or less of mRNA at a dosing interval of once every two weeks or a longer dosing internal for a period sufficient to treat at least one symptom or reduce the level of a biomarker associated with ornithine transcarbamylase deficiency in the human relative to a control.

2. The method of claim 1 , wherein the therapeutic low dose is 0.4 mg/kg or less, or 0.3 mg/kg or less, or 0.2 mg/kg or less, or 0.15 mg/kg less, or 0.10 mg/kg or less, or 0.05 mg/kg or less, or 0.01 mg/kg or less, of mRNA encoding ornithine transcarbamylase protein.

3. The method of claim 1 , wherein the longer dosing interval is once every three weeks or longer, or once every 4 weeks or longer.

4. The method of claim 1 , wherein the mRNA is codon optimized.

5. The method of claim 1 , wherein the symptom comprises hyperammonemia.

6. The method of claim 1 , wherein the biomarker is selected from the group consisting of: high plasma ammonia level, high tissue ammonia level, urinary orotic acid, citrulline, serum glutamate, brain myoinositol, serum amino acids, and combination thereof.

7. The method of claim 1 , wherein the mRNA is encapsulated in the lipid nanoparticle.

8. The method of claim 1 , wherein the lipid nanoparticle comprises one or more cationic lipids.

9. The method of claim 1 , wherein the lipid nanoparticle comprises one or more non-cationic lipids.

10. The method of claim 1 , wherein the lipid nanoparticle comprises one or more PEGylated lipids.

11. The method of claim 1 , wherein the pharmaceutical composition further comprises one or more excipients.

12. The method of claim 1 , wherein the mRNA comprises one or more modified nucleotides.

13. The method of claim 1 , wherein the administering of the pharmaceutical composition is performed intravenously.

14. The method of claim 1 , wherein the mRNA is administered concurrently with an additional therapy.

15. The method of claim 1 , wherein the administration results in distribution of the mRNA to the liver.

16. The method of claim 1 , wherein the mRNA comprises a polynucleotide sequence at least 80% identical to SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

17. The method of claim 1 , wherein the mRNA comprises a polynucleotide sequence at least 90% identical to SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10.

18. The method of claim 1 , wherein the mRNA encodes an ornithine transcarbamylase protein comprising at least 90% identity to the amino acid of SEQ ID NO: 3.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 3, 2025
From: ASKEW, KIM; CHUNG, JOU-KU; DEROSA, FRANK; HEARTLEIN, MICHAEL; KARVE, SHRIRANG; MCCAULEY, THOMAS; SMITH, LIANNE; BARBIER, ANN J.
To: TRANSLATE BIO MA, INC.
Reel/Frame 070377/0082 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 26, 2021
From: TRANSLATE BIO MA, INC.
To: TRANSLATE BIO, INC.
Reel/Frame 057920/0614 →
Continuity (3)
Division 16228596 · Dec 20, 2018
Provisional Application 62608547 · Dec 20, 2017
Related Publication 20220072152A1 · Mar 10, 2022
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