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

Abstract

Key Points New LVs allow transduction of unstimulated hematopoietic stem cells.

Measles virus envelope pseudotyped lentiviral vectors transduce quiescent human HSCs at an efficiency without precedent

“…Importantly, the H/F-LVs were able to efficiently transduce unstimulated hCD34 1 cells at levels not reported before (40% to 70%) after a single exposure at low vector doses (MOI, 10; Figure 2A). As we previously described, 12,42,43 the VSV-G-LVs were unable to transduce efficiently resting hCD34 1 cells (Figure 2A). In contrast to cytokine-prestimulated hCD34 1 cells, their resting counterparts require at least an MOI of 10 for efficient H/F-LV transduction ( Figure 1E-F vs Figure 2B).…”

“…44,66,68,69 Very recently we demonstrated that a new LV pseudotype carrying the Baboon envelope gp's at their surface (BaEV-LVs) outperformed VSV-G-LVs for hHSC transduction. 43 BaEV-LVs and H/F-LVs manage to transduce resting hHSCs up to 30% and 70%, respectively. H/F-LVs achieved transduction levels never before reached in these resting targets.…”

“…This means that the H/F-LVs overcome an important barrier for clinical gene therapy using VSV-G-LVs, which demonstrate limited efficiency in particular in resting HSCs. 12,35,60,61 It is essential to transduce HSCs without changing their capacity for self-renewal, homing, and differentiation, which is supported by minimal or no stimulation of these targets. Moreover, cytokine stimulation induces HSCs to exit their quiescent state accompanied by induction of DNA damage in these cells.…”

Stem cell manipulation, gene therapy and the risk of cancer stem cell emergence

“…Therefore, a high viral exposure combined to cytokine stimulation could promote mutagenesis and multicopy integration (44). As an alternative strategy, the recent use of a lentiviral vector pseudo-typed with a baboon retroviral envelope glycoprotein resulted in a higher transduction efficiency in quiescent CD34 + , at a low concentration without any cytokine stimulation (53). Altogether, the safety of these different approaches remains questionable.…”

Envelope, please. And the award goes to…

“…1 A utologous transplantation using genecorrected HSCs is achieving a growing number of clinical successes for the treatment of primary immune deficiencies, lysosomal storage and metabolic disorders, and hemoglobinopathies. 2,3 Despite the gratifying progress, it remains challenging to achieve optimal gene transfer to human HSCs, and 10-to 100-fold higher amounts of vectors are typically needed for their gene modification different envelopes to pseudotype the vectors for optimal target HSC binding and entry.…”