TY - JOUR
T1 - Therapeutic liver repopulation by transient acetaminophen selection of gene-modified hepatocytes
AU - Vonada, Anne
AU - Tiyaboonchai, Amita
AU - Nygaard, Sean
AU - Posey, Jeffrey
AU - Peters, Alexander Mack
AU - Winn, Shelley R.
AU - Cantore, Alessio
AU - Naldini, Luigi
AU - Harding, Cary O.
AU - Grompe, Markus
N1 - Publisher Copyright:
© 2021 The Authors, some rights reserved;
PY - 2021/6/9
Y1 - 2021/6/9
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.abg3047
DO - 10.1126/scitranslmed.abg3047
M3 - Article
C2 - 34108249
AN - SCOPUS:85107829748
SN - 1946-6234
VL - 13
JO - Science translational medicine
JF - Science translational medicine
IS - 597
M1 - eabg3047
ER -