title: Correction of murine Bernard-Soulier syndrome by lentivirus-mediated gene therapy.
abstract: 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 GPIbα (hGPIbα) in human megakaryocytes using a lentiviral vector (LV) encoding human GP1BA under control of the platelet-specific integrin αIIb promoter (2bIbα). In this study, we examined the efficacy of this strategy for the gene therapy of BSS using GPIbα(null) as a murine model of BSS. GPIbα(null) hematopoietic stem cells (HSC) transduced with 2bIbα LV were transplanted into lethally irradiated GPIbα(null) littermates. Therapeutic levels of hGPIbα expression were achieved that corrected the tail bleeding time and improved the macrothrombocytopenia. Sequential bone marrow (BM) transplants showed sustained expression of hGPIbα with similar phenotypic correction. Antibody response to hGPIbα 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.
authors: Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors: Sachiko
authors: S
authors: Kanaji
authors: Erin L
authors: EL
authors: Kuether
authors: Scot A
authors: SA
authors: Fahs
authors: Jocelyn A
authors: JA
authors: Schroeder
authors: Jerry
authors: J
authors: Ware
authors: Robert R
authors: RR
authors: Montgomery
authors: Qizhen
authors: Q
authors: Shi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000097:blood / Q000276:immunology; D001606:Bernard-Soulier Syndrome / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D001792:Blood Platelets / Q000378:metabolism; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D015870:Gene Expression; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006470:Hemorrhage / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D019038:Platelet Glycoprotein GPIb-IX Complex; D011485:Protein Binding; D013921:Thrombocytopenia / Q000276:immunology
chemical_list: D000906:Antibodies; D008562:Membrane Glycoproteins; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor