| First Author | Vonada A | Year | 2021 |
| Journal | Sci Transl Med | Volume | 13 |
| Issue | 597 | PubMed ID | 34108249 |
| Mgi Jnum | J:330069 | Mgi Id | MGI:6728692 |
| Doi | 10.1126/scitranslmed.abg3047 | Citation | Vonada A, et al. (2021) Therapeutic liver repopulation by transient acetaminophen selection of gene-modified hepatocytes. Sci Transl Med 13(597) |
| abstractText | 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. |
