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PMID: 15972454 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Therapeutic expression of the platelet-specific integrin, alphaIIbbeta3, in a murine model for Glanzmann thrombasthenia.

Blood ·Vol. 106 ·No. 8 ·2005-10-15 ·Pages 2671-9

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

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.

MeSH Terms
Animals Blood Platelets/metabolism Disease Models, Animal Genetic Therapy Humans Immunoglobulins/blood,immunology Mice Organ Specificity Platelet Aggregation Platelet Glycoprotein GPIIb-IIIa Complex/genetics,metabolism,therapeutic use Promoter Regions, Genetic/genetics Thrombasthenia/genetics,metabolism,pathology,therapy
Chemicals
Immunoglobulins Platelet Glycoprotein GPIIb-IIIa Complex
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Fang Juan
Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226, USA.
Hodivala-Dilke Kairbaan
Johnson Bryon D
Du Lily M
Hynes Richard O
White Gilbert C
Wilcox David A
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2004-12-4619
Published
2005-10-15
Epub
2005-00-21
Pages
2671-9
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895311
Subset
IM
Grants
NHLBI NIH HHS · HL-68138 · United States
NHLBI NIH HHS · P01-HL45100 · United States
NHLBI NIH HHS · P01-HL66105 · United States
External Links
PubMed source DOI: 10.1182/blood-2004-12-4619 PMC Full Text View journal details
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