These authors contributed equally to this work.
Article first published online: 27 MAY 2013
Copyright © 2012 American Association for the Study of Liver Diseases
Volume 58, Issue 1, pages 397–408, July 2013
How to Cite
Rittelmeyer, I., Rothe, M., Brugman, M. H., Iken, M., Schambach, A., Manns, M. P., Baum, C., Modlich, U. and Ott, M. (2013), Hepatic lentiviral gene transfer is associated with clonal selection, but not with tumor formation in serially transplanted rodents. Hepatology, 58: 397–408. doi: 10.1002/hep.26204
Potential conflict of interest: Nothing to report.
Supported by grants of the Deutsche Forschungsgemeinschaft (SFB 738 and the Excellence Cluster REBIRTH).
- Issue published online: 24 JUN 2013
- Article first published online: 27 MAY 2013
- Accepted manuscript online: 19 DEC 2012 11:42AM EST
- Manuscript Accepted: 11 DEC 2012
- Manuscript Received: 18 SEP 2012
Lentiviral (LV) vectors are promising tools for long-term genetic correction of hereditary diseases. In hematopoietic stem cell gene therapies adverse events in patients due to vector integration-associated genotoxicity have been observed. Only a few studies have explored the potential risks of LV gene therapy targeting the liver. To analyze hepatic genotoxicity in vivo, we transferred the fumarylacetoacetate hydrolase (FAH) gene by LV vectors into FAH(-/-) mice (n = 97) and performed serial hepatocyte transplantations (four generations). The integration profile (4,349 mapped insertions) of the LV vectors was assessed by ligation-mediated polymerase chain reaction and deep sequencing. We tested whether the polyclonality of vector insertions was maintained in serially transplanted mice, linked the integration sites to global hepatocyte gene expression, and investigated the effects of LV liver gene therapy on the survival of the animals. The lifespan of in vivo gene-corrected mice was increased compared to 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) control animals and unchanged in serially transplanted animals. The integration profile (4,349 mapped insertions) remained polyclonal through all mouse generations with only mild clonal expansion. Genes close to the integration sites of expanding clones may be associated with enhanced hepatocyte proliferation capacity. Conclusion: We did not find evidence for vector-induced tumors. LV hepatic gene therapy showed a favorable risk profile for stable and long-term therapeutic gene expression. Polyclonality of hepatocyte regeneration was maintained even in an environment of enforced proliferation. (HEPATOLOGY 2013)