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 alpha- or beta-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, alpha IIb beta 3, prevent platelet aggregation following vascular injury. We previously used a retrovirus vector containing a cDNA cassette encoding human integrin beta 3 to restore integrin alpha IIb beta 3 on the surface of megakaryocytes derived from peripheral blood stem cells of GT patients. In the present study, bone marrow from beta 3-deficient (beta 3(-/-)) mice was transduced with the ITG beta 3-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 beta 3 formed a stable complex with murine alpha IIb, effectively restoring platelet function. Mice expressing significant levels of alpha IIb beta 3 on circulating platelets exhibited improved bleeding times. Intravenous immunoglobulin effectively diminished platelet clearance in animals that developed an antibody response to alpha IIb beta 3. These results indicate the feasibility of targeting platelets with genetic therapies for better management of patients with inherited bleeding disorders.