| Autor: |
Robert Allen, Kaiser, Clara Teresa, Nicolas, Kari Lynn, Allen, Jennifer Anne, Chilton, Zeji, Du, Raymond Daniel, Hickey, Joseph Benjamin, Lillegard |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Hum Gene Ther Clin Dev |
| ISSN: |
2324-8645 |
| Popis: |
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/CCl(4))–induced liver injury mice to assess specific toxicity in fibrotic liver tissue. Mice receiving LV-FAH alone (10(9) TU/mouse) or in combination with DEN/CCl(4) 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/CCl(4) 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/CCl(4)-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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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