hInGeTox: A human-based in vitro platform to evaluate lentivirus contribution to genotoxicity

Abstract

Abstract Lentivirus vectors are effective for treatment of genetic disease and cancer, however, vector related insertional mutagenesis related genotoxicity is of concern and currently available safety models are not reliably predictive of safety in humans. We have developed hInGeTox as the first human in vitro platform that uses induced pluripotent stem cells and their hepatocyte like derivatives to further understand LV host interaction for vector safety evaluation and design. To characterise LV for genotoxic association, we used LTR and SIN configuration LV infected cells for a multi-omics analysis on data that included LV integration sites in cancer genes and their associated differential expression, clonal tracking of IS, novel vector/host fusion transcripts and methylated cancer genes with altered gene expression after infection. We present hInGeTox as a useful pre-clinical tool to identify lentivirus contributory factors mediating genotoxicity to use for improving LV design to provide gene therapy.