Plenary Paper GENE THERAPY Baboon envelope pseudotyped LVs outperform VSV-G-LVs for gene transfer into early-cytokine-stimulated and resting HSCs

New LVs allow transduction of unstimulated hematopoietic stem cells. Hematopoietic stem cell (HSC)-based gene therapy holds promise for the cure of many diseases. The field is nowmoving toward the use of lentiviral vectors (LVs) as evidenced by 4 successful clinical trials. These trials used vesicular-stomatitis-virus-G protein (VSV-G)-LVs at high doses combinedwith strong cytokine-cocktail stimulation to obtain therapeutically relevant transduction levels; however, theymight compromise theHSC 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 a low dose, resulted in up to 90 % of hCD341 cell transduction. Even more striking was that these new BaEV-LVs allowed, at low doses, efficient transduction of up to 30 % of quiescent hCD341 cells, whereas high-dose VSV-G-LVs were insufficient. Importantly, recon