Hepatotoxicity and Toxicology of In Vivo Lentiviral Vector Administration in Healthy and Liver-Injury Mouse Models

Robert Allen Kaiser, Clara Teresa Nicolas, Kari Lynn Allen, Jennifer Anne Chilton, Zeji Du, Raymond Daniel Hickey, Joseph Benjamin Lillegard

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


General safety and toxicology assessments supporting in vivo lentiviral vector-based therapeutic development are sparse. We have previously demonstrated the efficacy of a lentiviral vector expressing fumarylacetoacetate hydrolase (LV-FAH) to cure animal models of hereditary tyrosinemia type 1. Therefore, we performed a complete preclinical toxicological evaluation of LV-FAH, in a large cohort (n = 20/group) of wildtype mice and included matched groups of N-nitrosodiethylamine/carbon tetrachloride (DEN/CCl4)-induced liver injury mice to assess specific toxicity in fibrotic liver tissue. Mice receiving LV-FAH alone (109 TU/mouse) or in combination with DEN/CCl4 presented clinically similar to control animals, with only slight reductions in total body weight gains over the study period (3.2- to 3.7-fold vs. 4.2-fold). There were no indications of toxicity attributed to administration of LV-FAH alone over the duration of this study. The known hepatotoxic combination of DEN/CCl4 induced fibrotic liver injury, and co-administration with LV-FAH was associated with exaggeration of some findings such as an increased liver:body weight ratio and progression to focal hepatocyte necrosis in some animals. Hepatocellular degeneration/regeneration was present in DEN/CCl4-dosed animals regardless of LV-FAH as evaluated by Ki-67 immunohistochemistry and circulating alpha fetoprotein levels, but there were no tumors identified in any tissue in any dose group. These data demonstrate the inherent safety of LV-FAH and support broader clinical development of lentiviral vectors for in vivo administration.

Original languageEnglish (US)
Pages (from-to)57-66
Number of pages10
JournalHuman Gene Therapy Clinical Development
Issue number2
StatePublished - Jun 2019


  • gene therapy
  • hereditary tyrosinemia type 1
  • lentiviral vectors
  • toxicology
  • tumorigenicity

ASJC Scopus subject areas

  • Genetics(clinical)


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