Mechanisms of enhanced HSC transduction and nucleic acid sensing

Current hematopoietic stem and progenitor cell (HSPC) gene therapy protocols require the use of multiple hits at high vector doses and prolonged ex vivo culture to reach clinically relevant transduction levels, imposing large-scale vector production and potentially compromising HSPC preservation in culture. Therefore, improving LV transduction efficiency in HSPC remains a high priority goal for the field. With this general objective in mind, this Research Project proposal aims to characterize the molecular mechanisms of LV restriction in HSPC and investigate the impact LV transduction and, more broadly, nucleic acid sensing have in different disease settings. Up to date, our studies on vector-host interactions have uncovered substantial differences in how HSC sense distinct viral vectors and identified a potent innate immune block to gene transfer constitutively active in HSC, leading to the development of novel, highly efficient gene therapy approaches. We are currently investigating LV-mediated signaling and nucleic acid sensing in inflammatory disease backgrounds for more stealth gene transfer and work on identifying the molecular partners involved restriction of lentiviral transduction in HSPC. Overall, our efforts to understand the crosstalk between HSPC and viral vectors instructs us on which immune sensors and effectors to avoid and how, providing means to maximize gene engineering efficiencies and curb donor variability while preserving HSC biological properties.