Language

English

Publication Date

2-12-2025

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.adk3920

PMID

39937884

PMCID

PMC13690267

PubMedCentral® Posted Date

10-23-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Homology directed repair (HDR)-based genome editing is an approach that could permanently correct a broad range of genetic diseases. However, its utility is limited by inefficient and imprecise DNA repair mechanisms in terminally differentiated tissues. Here, we tested “Repair Drive”, a platform technology for selectively expanding HDR-corrected hepatocytes in adult mice in vivo. Repair Drive involves transient conditioning of the liver by knocking down an essential gene – fumarylacetoacetate hydrolase (Fah), and delivery of an untargetable version of the essential gene in cis with a therapeutic transgene. We show that Repair Drive increased the percentage of correctly targeted hepatocytes in healthy wild type mice up to 25%. This resulted in a five-fold increased expression of a therapeutic transgene, human Factor IX (FIX). Repair Drive was well-tolerated and did not induce toxicity or tumorigenesis in 1-year long follow up. This approach may broaden the range of liver diseases that can be treated with somatic genome editing.

Keywords

Animals, Hepatocytes, Humans, Genes, Essential, Mice, Gene Targeting, Gene Editing, Hydrolases, Transgenes, Liver, DNA Repair, Mice, Inbred C57BL

Published Open-Access

yes

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