| Autor: |
Hu P; Gene Therapy Center, University of North Carolina at Chapel Hill, 27599 Chapel Hill, North Carolina, USA.; These authors contributed equally., Hao Y; Department of Biostatistics, University of North Carolina at Chapel Hill, 27599 Chapel Hill, North Carolina, USA.; These authors contributed equally., Tang W; Gene Therapy Center, University of North Carolina at Chapel Hill, 27599 Chapel Hill, North Carolina, USA., Diering GH; Department of Cell Biology and Physiology and UNC Neuroscience Center, University of North Carolina at Chapel Hill, 27599 Chapel Hill, North Carolina, USA.; Carolina Institute for developmental disabilities, 27510 Carrboro, North Carolina., Zou F; Department of Biostatistics, University of North Carolina at Chapel Hill, 27599 Chapel Hill, North Carolina, USA.; Department of Genetics, University of North Carolina at Chapel Hill, 27599 Chapel Hill, North Carolina, USA., Kafri T; Gene Therapy Center, University of North Carolina at Chapel Hill, 27599 Chapel Hill, North Carolina, USA.; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, 27599 Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, 27599 Chapel Hill, North Carolina. |
| Abstrakt: |
Lentiviral vector-transduced T-cells were approved by the FDA as gene therapy anti-cancer medications. Little is known about the host genetic variation effects on the safety and efficacy of the lentiviral vector gene delivery system. To narrow this knowledge-gap, we characterized hepatic gene delivery by lentiviral vectors across the Collaborative Cross (CC) mouse genetic reference population. For 24 weeks, we periodically measured hepatic luciferase expression from lentiviral vectors in 41 CC mouse strains. Hepatic and splenic vector copy numbers were determined. We report that CC mouse strains showed highly diverse outcomes following lentiviral gene delivery. For the first time, moderate correlation between mouse strain-specific sleeping patterns and transduction efficiency was observed. We associated two quantitative trait loci (QTLs) with intra-strain variations in transduction phenotypes, which mechanistically relates to the phenomenon of metastable epialleles. An additional QTL was associated with the kinetics of hepatic transgene expression. Genes comprised in the above QTLs are potential targets to personalize gene therapy protocols. Importantly, we identified two mouse strains that open new directions in characterizing continuous viral vector silencing and HIV latency. Our findings suggest that wide-range patient-specific outcomes of viral vector-based gene therapy should be expected. Thus, novel escalating dose-based clinical protocols should be considered. |
