Granted Patent B2

US 12,533,424 · App. 18/959,371 · Granted Jan 27, 2026

Inventors: Brian C. Thomas (Berkeley, CA); Alan Brooks (Clayton, CA)

Assignee: Metagenomi, Inc.

A61K48/005A61K9/1272A61K9/5123A61K38/37C12N5/067C12N9/22C12N15/111C12N15/86C12N15/88C12N15/907C12N2310/20C12N2750/14143

Abstract

Claims (10)

1 . A method for supplementing liver enzyme expression in a subject in need thereof, comprising administering to the subject:

a) an endonuclease having the amino acid sequence of SEQ ID NO: 54;

b) an engineered guide polynucleotide capable of i) forming a complex with the endonuclease and ii) hybridizing to a target nucleic acid sequence within intron 1 of an albumin gene; and

c) a donor template polynucleotide comprising a nucleic acid encoding a Factor VIII (FVIII) gene or a functional fragment thereof, thereby supplementing liver enzyme expression of Factor VIII in said subject, the nucleic acid having at least 98% sequence identity to any one of SEQ ID NOs: 12, 13, 16-23, 32, 33, or 56-59.

2 . The method of claim 1 , wherein the endonuclease is encoded by a nucleic acid having 100% sequence identity to any one of SEQ ID NOs: 31 or 53.

3 . The method of claim 1 , wherein the engineered guide polynucleotide has at least 90% sequence identity to any one of SEQ ID NOs: 14, 15, 24-27, 43-45, 50, 55, or 60-68.

4 . The method of claim 1 , wherein the target nucleic acid sequence has at least 90% or 100% sequence identity to any one of SEQ ID NOs: 1, 2-6, or 8.

5 . The method of claim 1 , wherein the nucleic acid has at least 90100% sequence identity to any one of SEQ ID NOs: 12, 13, 16-23, 32, 33, or 56-59.

6 . The method of claim 1 , wherein the FVIII gene or functional fragment thereof is codon-optimized to remove at least one cytosine-guanine (CG or CpG) motif.

7 . The method of claim 1 , wherein the FVIII gene or functional fragment thereof has at least 98% identity to SEQ ID NO: 10 and is modified to comprise a B-domain.

Assignments (2)

Continuity (5)

References Cited (81)