Correction of Murine Bernard-Soulier Syndrome by Lentivirus-mediated Gene Therapy

Bernard-Soulier syndrome (BSS) is an inherited bleeding disorder caused by a defect in the platelet glycoprotein (GP) Ib-IX-V complex. The main treatment for BSS is platelet transfusion but it is often limited to severe bleeding episodes or surgical interventions due to the risk of alloimmunization. We have previously reported successful expression of human GPIb alpha (hGPIb alpha) in human mega-karyocytes using a lentiviral vector (LV) encoding human GP1BA under control of the platelet-specific integrin alpha IIb promoter (2bIb alpha). In this study, we examined the efficacy of this strategy for the gene therapy of BSS using GPIb alpha(null) as a murine model of BSS. GPIb alpha(null) hematopoietic stem cells (HSC) transduced with 2bIb alpha LV were transplanted into lethally irradiated GPIb alpha(null) littermates. Therapeutic levels of hGPIb alpha expression were achieved that corrected the tail bleeding time and improved the macrothrombocytopenia. Sequential bone marrow (BM) transplants showed sustained expression of hGPIb alpha with similar phenotypic correction. Antibody response to hGPIb alpha was documented in 1 of 17 total recipient mice but was tolerated without any further treatment. These results demonstrate that lentivirus-mediated gene transfer can provide sustained phenotypic correction of murine BSS, indicating that this approach may be a promising strategy for gene therapy of BSS patients. Received 28 June 2011; accepted 28 September 2011; published online 1 November 2011. doi:10.1038/mt.2011.231