bioRxiv : the preprint server for biology · 2023
In vivo expansion of gene-targeted hepatocytes through transient inhibition of an essential gene.
ПрепринтСтатьяНазвание и аннотация: Перевод пока не подготовлен
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De Giorgi Marco, Park So Hyun, Castoreno Adam, Cao Mingming, Hurley Ayrea, Saxena Lavanya, Chuecos Marcel A, Walkey Christopher J, Doerfler Alexandria M, Furgurson Mia N, Ljungberg M Cecilia, Patel Kalyani R, Hyde Sarah, Chickering Tyler, Lefebvre Stephanie, Wassarman Kelly, Miller Patrick, Qin June, Schlegel Mark K, Zlatev Ivan, Li Rich Gang, Kim Jong, Martin James F, Bissig Karl-Dimiter, Jadhav Vasant, Bao Gang, Lagor William R
Аннотация
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 novel method for improving targeted gene insertion in the liver by selectively expanding correctly repaired hepatocytes in vivo. Our system consists of transient conditioning of the liver by knocking down an essential gene, 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. 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.