Platelet gene therapy improves hemostatic function for integrin αIIbβ3-deficient dogs

Juan Fang, Eric S. Jensen, Mary K. Boudreaux, Lily M. Du, Troy B. Hawkins, Sevasti B. Koukouritaki, Kenneth Cornetta, David A. Wilcox

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 pre-transplant 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.

Original languageEnglish
Pages (from-to)9583-9588
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number23
DOIs
StatePublished - Jun 7 2011

Fingerprint

Hemostatics
Integrins
Genetic Therapy
Blood Platelets
Dogs
Thrombasthenia
Hemorrhage
Transplants
Bleeding Time
Cheek
Vascular System Injuries
Disease Susceptibility
Homologous Transplantation
Hematopoietic Stem Cells
Fibrin
Bone Marrow Transplantation
Fibrinogen
Antibody Formation
Canidae
Ligands

Keywords

  • Hematology
  • Hemostasis
  • Recombinant lentivirus-mediated gene transfer

ASJC Scopus subject areas

  • General

Cite this

Fang, J., Jensen, E. S., Boudreaux, M. K., Du, L. M., Hawkins, T. B., Koukouritaki, S. B., ... Wilcox, D. A. (2011). Platelet gene therapy improves hemostatic function for integrin αIIbβ3-deficient dogs. Proceedings of the National Academy of Sciences of the United States of America, 108(23), 9583-9588. https://doi.org/10.1073/pnas.1016394108

Platelet gene therapy improves hemostatic function for integrin αIIbβ3-deficient dogs. / Fang, Juan; Jensen, Eric S.; Boudreaux, Mary K.; Du, Lily M.; Hawkins, Troy B.; Koukouritaki, Sevasti B.; Cornetta, Kenneth; Wilcox, David A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 23, 07.06.2011, p. 9583-9588.

Research output: Contribution to journalArticle

Fang, Juan ; Jensen, Eric S. ; Boudreaux, Mary K. ; Du, Lily M. ; Hawkins, Troy B. ; Koukouritaki, Sevasti B. ; Cornetta, Kenneth ; Wilcox, David A. / Platelet gene therapy improves hemostatic function for integrin αIIbβ3-deficient dogs. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 23. pp. 9583-9588.
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