Phagocytosis-shielded lentiviral vectors improve liver gene therapy in nonhuman primates.

Liver-directed gene therapy for the coagulation disorder hemophilia showed safe and effective results in clinical trials using adeno-associated viral vectors to replace a functional coagulation factor, although some unmet needs remain. Lentiviral vectors (LVs) may address some of these hurdles because of their potential for stable expression and the low prevalence of preexisting viral immunity in humans. However, systemic LV administration to hemophilic dogs was associated to mild acute toxicity and low efficacy at the administered doses.

Genome editing for scalable production of alloantigen-free lentiviral vectors for gene therapy.

Lentiviral vectors (LV) are powerful and versatile vehicles for gene therapy. However, their complex biological composition challenges large-scale manufacturing and raises concerns for applications, because particle components and contaminants may trigger immune responses. Here, we show that producer cell-derived polymorphic class-I major histocompatibility complexes (MHC-I) are incorporated into the LV surface and trigger allogeneic T-cell responses.

Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells.

Clinical application of lentiviral vector (LV)-based hematopoietic stem and progenitor cells (HSPC) gene therapy is rapidly becoming a reality. Nevertheless, LV-mediated signaling and its potential functional consequences on HSPC biology remain poorly understood. We unravel here a remarkably limited impact of LV on the HSPC transcriptional landscape.

Cyclosporin a and rapamycin relieve distinct lentiviral restriction blocks in hematopoietic stem and progenitor cells.

Improving hematopoietic stem and progenitor cell (HSPC) permissiveness to HIV-derived lentiviral vectors (LVs) remains a challenge for the field of gene therapy as high vector doses and prolonged ex vivo culture are still required to achieve clinically relevant transduction levels. We report here that Cyclosporin A (CsA) and Rapamycin (Rapa) significantly improve LV gene transfer in human and murine HSPC. Both compounds increased LV but not gammaretroviral transduction and acted independently of calcineurin and autophagy.

Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice.

A major complication of factor replacement therapy for haemophilia is the development of anti-factor neutralizing antibodies (inhibitors). Here we show that liver gene therapy by lentiviral vectors (LVs) expressing factor IX (FIX) strongly reduces pre-existing anti-FIX antibodies and eradicates FIX inhibitors in haemophilia B mice. Concomitantly, plasma FIX levels and clotting activity rose to 50-100% of normal.