Faculty Collaboration Database

Therapeutic expression of the platelet-specific integrin, alphaIIbbeta3, in a murine model for Glanzmann thrombasthenia. Blood 2005 Oct 15;106(8):2671-9

Date

06/24/2005

Pubmed ID

15972454

Pubmed Central ID

PMC1895311

DOI

10.1182/blood-2004-12-4619

Scopus ID

2-s2.0-27144537145 (requires institutional sign-in at Scopus site)   83 Citations

Abstract

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, alphaIIbbeta3, prevent platelet aggregation following vascular injury. We previously used a retrovirus vector containing a cDNA cassette encoding human integrin beta3 to restore integrin alphaIIbbeta3 on the surface of megakaryocytes derived from peripheral blood stem cells of GT patients. In the present study, bone marrow from beta3-deficient (beta3-/-) mice was transduced with the ITGbeta3-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 beta3 formed a stable complex with murine alphaIIb, effectively restoring platelet function. Mice expressing significant levels of alphaIIbbeta3 on circulating platelets exhibited improved bleeding times. Intravenous immunoglobulin effectively diminished platelet clearance in animals that developed an antibody response to alphaIIbbeta3. These results indicate the feasibility of targeting platelets with genetic therapies for better management of patients with inherited bleeding disorders.

Author List

Fang J, Hodivala-Dilke K, Johnson BD, Du LM, Hynes RO, White GC 2nd, Wilcox DA

Authors

Bryon D. Johnson PhD Adjunct Professor in the Medicine department at Medical College of Wisconsin
Gilbert C. White MD Professor in the Medicine department at Medical College of Wisconsin
David A. Wilcox PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Platelets
Disease Models, Animal
Genetic Therapy
Humans
Immunoglobulins
Mice
Organ Specificity
Platelet Aggregation
Platelet Glycoprotein GPIIb-IIIa Complex
Promoter Regions, Genetic
Thrombasthenia