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Platelet gene therapy corrects the hemophilic phenotype in immunocompromised hemophilia A mice transplanted with genetically manipulated human cord blood stem cells.

Abstract
Our previous studies have demonstrated that platelet FVIII (2bF8) gene therapy can improve hemostasis in hemophilia A mice, even in the presence of inhibitory antibodies, but none of our studies has targeted human cells. Here, we evaluated the feasibility for lentivirus (LV)-mediated human platelet gene therapy of hemophilia A. Human platelet FVIII expression was introduced by 2bF8LV-mediated transduction of human cord blood (hCB) CD34(+) cells followed by xenotransplantation into immunocompromised NSG mice or NSG mice in an FVIII(null) background (NSGF8KO). Platelet FVIII was detected in all recipients that received 2bF8LV-transduced hCB cells as long as human platelet chimerism persisted. All NSGF8KO recipients (n = 7) that received 2bF8LV-transduced hCB cells survived tail clipping if animals had greater than 2% of platelets derived from 2bF8LV-transduced hCB cells, whereas 5 of 7 survived when human platelets were 0.3% to 2%. Whole blood clotting time analysis confirmed that hemostasis was improved in NSGF8KO mice that received 2bF8LV-transduced hCB cells. We demonstrate, for the first time, the feasibility of 2bF8LV gene delivery to human hematopoietic stem cells to introduce FVIII expression in human platelets and that human platelet-derived FVIII can improve hemostasis in hemophilia A.
AuthorsQizhen Shi, Erin L Kuether, Yingyu Chen, Jocelyn A Schroeder, Scot A Fahs, Robert R Montgomery
JournalBlood (Blood) Vol. 123 Issue 3 Pg. 395-403 (Jan 16 2014) ISSN: 1528-0020 [Electronic] United States
PMID24269957 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, CD34
  • Factor VIII
Topics
  • Animals
  • Antigens, CD34 (metabolism)
  • Blood Platelets (cytology, metabolism)
  • Chimerism
  • Cord Blood Stem Cell Transplantation
  • Factor VIII (metabolism)
  • Fetal Blood (metabolism)
  • Gene Expression Regulation
  • Genetic Therapy
  • Hemophilia A (genetics, therapy)
  • Humans
  • Immunohistochemistry
  • Lentivirus (genetics, metabolism)
  • Mice
  • Mice, Knockout
  • Mice, SCID
  • Phenotype
  • Thrombopoiesis

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