Faculty Collaboration Database

Platelet gene therapy improves hemostatic function for integrin alphaIIbbeta3-deficient dogs. Proc Natl Acad Sci U S A 2011 Jun 07;108(23):9583-8

Date

05/25/2011

Pubmed ID

21606353

Pubmed Central ID

PMC3111318

DOI

10.1073/pnas.1016394108

Scopus ID

2-s2.0-79959329020 (requires institutional sign-in at Scopus site)   52 Citations

Abstract

Activated blood platelets mediate the primary response to vascular injury. Although molecular abnormalities of platelet proteins occur infrequently, taken collectively, an inherited platelet defect accounts for a bleeding diathesis in ≈1:20,000 individuals. One rare example of a platelet disorder, Glanzmann thrombasthenia (GT), is characterized by life-long morbidity and mortality due to molecular abnormalities in a major platelet adhesion receptor, integrin αIIbβ3. Transfusion therapy is frequently inadequate because patients often generate antibodies to αIIbβ3, leading to immune-mediated destruction of healthy platelets. In the most severe cases allogeneic bone marrow transplantation has been used, yet because of the risk of the procedure it has been limited to few patients. Thus, hematopoietic stem cell gene transfer was explored as a strategy to improve platelet function within a canine model for GT. Bleeding complications necessitated the use of a mild pretransplant conditioning regimen; therefore, in vivo drug selection was used to improve engraftment of autologously transplanted cells. Approximately 5,000 αIIbβ3 receptors formed on 10% of platelets. These modest levels allowed platelets to adhere to αIIbβ3's major ligand (fibrinogen), form aggregates, and mediate retraction of a fibrin clot. Remarkably, improved hemostatic function was evident, with ≤135-fold reduced blood loss, and improved buccal bleeding times decreased to 4 min for up to 5 y after transplant. One of four transplanted dogs developed a significant antibody response to αIIbβ3 that was attenuated effectively with transient immune suppression. These results indicate that gene therapy could become a practical approach for treating inherited platelet defects.

Author List

Fang J, Jensen ES, Boudreaux MK, Du LM, Hawkins TB, Koukouritaki SB, Cornetta K, Wilcox DA

Authors

Eric S. Jensen DVM Associate Professor in the Research Office department at Medical College of Wisconsin
Sevasti Koukouritaki Research Scientist II in the Pediatrics 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
Antigens, CD34
Bleeding Time
Blood Platelets
Cell Transplantation
Cells, Cultured
Dog Diseases
Dogs
Flow Cytometry
Genetic Therapy
Hemostasis
Humans
Leukocytes, Mononuclear
Mouth Mucosa
Platelet Glycoprotein GPIIb-IIIa Complex
Thrombasthenia
Transfection
Transplantation, Autologous