Therapeutic liver repopulation by transient acetaminophen selection of gene-modified hepatocytes
Anne Vonada, Amita Tiyaboonchai, Sean Nygaard, Jeffrey Posey, A. Mack Peters, Shelley R. Winn, Alessio Cantore, Luigi Naldini, Cary O. Harding, Markus Grompe
Abstract
shRNA were administered to neonatal mice. Hepatocytes lacking the essential cofactor of Cyp enzymes, NADPH-cytochrome p450 reductase (Cypor), were selected in vivo by acetaminophen administration, replacing up to 50% of the hepatic mass. Acetaminophen treatment of the mice resulted in over 30-fold expansion of transgene-bearing hepatocytes and achieved therapeutic thresholds in hemophilia B and phenylketonuria. We conclude that therapeutically modified hepatocytes can be selected safely and efficiently in preclinical models with a transient regimen of moderately hepatotoxic acetaminophen.