Research ArticleGene Therapy

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

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Science Translational Medicine  09 Jun 2021:
Vol. 13, Issue 597, eabg3047
DOI: 10.1126/scitranslmed.abg3047

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Trial by acetaminophen

Gene therapy vectors that integrate into the genome (as opposed to remaining episomal) promise sustained therapeutic effects for monogenic liver diseases in theory but typically do not integrate into sufficient numbers of hepatocytes to achieve therapeutic effects in practice. To increase therapeutic yields, Vonada et al. added a short hairpin RNA targeting Cypor, a cofactor necessary for acetaminophen metabolism, to integrating vectors to protect hepatocytes with successful transgene integration from toxicity related to acetaminophen exposure. Administration of the vector plus a moderately hepatotoxic dose of acetaminophen to neonatal mice achieved therapeutic degrees of viral vector integration in models of hemophilia B and phenylketonuria.

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