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Therapeutic expression of the platelet-specific integrin, αIIbβ3, in a murine model for Glanzmann thrombasthenia

Integrins mediate the adhesion of cells to each other and to the extracellular matrix during development, immunity, metastasis, thrombosis, and wound healing. Molecular defects in either the α- or β-subunit can disrupt integrin synthesis, assembly, and/or binding to adhesive ligands. This is exemplified by the bleeding disorder, Glanzmann thrombasthenia (GT), where abnormalities of the platelet-specific integrin, αIIbβ3, prevent platelet aggregation following vascular injury. We previously used a retrovirus vector containing a cDNA cassette encoding human integrin β3 to restore integrin αIIbβ3 on the surface of megakaryocytes derived from peripheral blood stem cells of GT patients. In the present study, bone marrow from β3-deficient (β3–/–) mice was transduced with the ITGβ3-cassette to investigate whether the platelet progeny could establish hemostasis in vivo. A lentivirus transfer vector equipped with the human ITGA2B gene promoter confined transgene expression to the platelet lineage. Human β3 formed a stable complex with murine αIIb, effectively restoring platelet function. Mice expressing significant levels of αIIbβ3 on circulating platelets exhibited improved bleeding times. Intravenous immunoglobulin effectively diminished platelet clearance in animals that developed an antibody response to αIIbβ3. These results indicate the feasibility of targeting platelets with genetic therapies for better management of patients with inherited bleeding disorders.