Therapeutic liver repopulation by transient acetaminophen selection of gene-modified hepatocytes

Anne Vonada, Amita Tiyaboonchai, Sean Nygaard, Jeffrey Posey, Alexander Mack Peters, Shelley R. Winn, Alessio Cantore, Luigi Naldini, Cary O. Harding, Markus Grompe

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Gene therapy by integrating vectors is promising for monogenic liver diseases, especially in children where episomal vectors remain transient. However, reaching the therapeutic threshold with genome-integrating vectors is challenging. Therefore, we developed a method to expand hepatocytes bearing therapeutic transgenes. The common fever medicine acetaminophen becomes hepatotoxic via cytochrome p450 metabolism. Lentiviral vectors with transgenes linked in cis to a Cypor 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.

Original languageEnglish (US)
Article numbereabg3047
JournalScience translational medicine
Issue number597
StatePublished - Jun 9 2021

ASJC Scopus subject areas

  • General Medicine


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