Baboon envelope pseudotyped lentiviral vectors outperform VSV-G pseudotyped lentiviral vectors for gene transfer into cytokine-stimulated and resting hematopoietic stem cells.

Affiliation ECOFECTInternational audience: Hematopoietic stem cell (HSC)-based gene therapy holds promise for the cure of many diseases. The field is now moving towards the use of lentiviral vectors (LVs) as evidenced by four successful clinical trials. These trials employed vesicular-stomatitis-virus-G protein (VSV-G)-LVs at high doses combined with strong cytokine-cocktail stimulation to obtain therapeutically relevant transduction levels but which might compromise the 'HSC' character. Summarizing all these disadvantages, alternatives to VSV-G-LVs are urgently needed. We generated here high-titer LVs pseudotyped with a baboon retroviral envelope glycoprotein (BaEV-LVs), resistant to human complement. Under mild cytokine-prestimulation to preserve the 'HSC' characteristics, a single BaEV-LV application at low dose, resulted in up to 90 % of hCD34(+)-cell transduction. Even more striking was that these new BaEV-LVs allowed at low doses efficient transduction of up to 30% of quiescent hCD34(+)-cells whereas high-dose VSV-G-LVs were insufficient. Importantly, reconstitution of NOD/Lt-SCID/γc(-/-)(NSG) mice with BaEV-LV transduced hCD34(+)-cells maintained these high transduction levels in all myeloid and lymphoid lineages including early progenitors. This transduction pattern was confirmed or even increased in secondary NSG recipient mice. This suggests that BaEV-LVs efficiently transduce true HSCs and could improve HSC-based gene therapy, for which high-level HSC correction is needed for life-long cure