Therapeutic expression of the platelet-specific integrin, IIb 3, 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 or 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 plateletspecific integrin, IIb 3, prevent platelet aggregation following vascular injury. We previously used a retrovirus vector containing a cDNA cassette encoding human integrin 3 to restore integrin IIb 3 on the surface of megakaryocytes derived from peripheral blood stem cells of GT patients. In the present study, bone marrow from 3-deficient ( 3 / ) mice was transduced with the ITG 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 3 formed a stable complex with murine IIb, effectively restoring platelet function. Mice expressing significant levels of IIb 3 on circulating platelets exhibited improved bleeding times. Intravenous immunoglobulin effectively diminished platelet clearance in animals that developed an antibody response to IIb 3. These results indicate the feasibility of targeting platelets with genetic therapies for better management of patients with inherited bleeding disorders. (Blood. 2005;106:2671-2679)