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In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene

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 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 dramatically increases the percentage of correctly targeted hepatocytes, 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 long-term follow up. This approach will broaden the range of liver diseases that can be treated with somatic genome editing.

ORGANISM(S): Mus musculus

PROVIDER: GSE277798 | GEO | 2024/09/23

REPOSITORIES: GEO

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