Baboon envelope pseudotyped lentiviral vectors transduce efficiently human B cells and allow active factor IX B cell secretion in vivo in NOD/SCID mice

SummaryBackground B cells are attractive targets for gene therapy of diseases associated with B-cell dysfunction and particularly interesting for immunotherapy. Moreover, B cells are potent protein-secreting cells and can be tolerogenic antigen presenting cells. Objective: Evaluation of human B cells for secretion of clotting factors such as factor IX (IX) as possible treatment for hemophilia. Methods We tested here for the first time our newly developed baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) for human (h) B-cell transduction followed their adaptive transfer into NSG mouse. Results Upon B-cell receptor stimulation, BaEV-LVs transduced up to 80% of hB cells, while VSV-G-LV only reached 5%. Remarkably, BaEVTR-LVs permitted efficient transduction of 20% of resting naive and 40% of resting memory B cells. Importantly, BaEV-LVs reached up to 100% transduction of human plasmocytes ex vivo. Adoptive transfer of BaEV-LV-transduced mature B cells into NOD/SCID/γ-/-(NSG) mice allowed differentiation into plasmablasts and plasma B cells confirming a sustained high-level gene marking in vivo. As proof of principle, we assessed BaEV-LV for transfer of human factor IX (hFIX) into B cells. BaEV-LVs encoding FIX efficiently transduced hB cells and their transfer into NSG mice demonstrated for the first time secretion of functional hFIX from hB cells at therapeutic levels in vivo. Conclusions The BaEV-LVs might represent a valuable tool for therapeutic protein secretion from autologous B cells in vivo in the treatment of hemophilia and other acquired or inherited diseases. This article is protected by copyright. All rights reserved.