Faculty Collaboration Database

Platelet gene therapy corrects the hemophilic phenotype in immunocompromised hemophilia A mice transplanted with genetically manipulated human cord blood stem cells. Blood 2014 Jan 16;123(3):395-403

Date

11/26/2013

Pubmed ID

24269957

Pubmed Central ID

PMC3894495

DOI

10.1182/blood-2013-08-520478

Scopus ID

2-s2.0-84897018747 (requires institutional sign-in at Scopus site)   42 Citations

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.

Author List

Shi Q, Kuether EL, Chen Y, Schroeder JA, Fahs SA, Montgomery RR

Authors

Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Qizhen Shi MD, 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
Blood Platelets
Chimerism
Cord Blood Stem Cell Transplantation
Factor VIII
Fetal Blood
Gene Expression Regulation
Genetic Therapy
Hemophilia A
Humans
Immunohistochemistry
Lentivirus
Mice
Mice, Knockout
Mice, SCID
Phenotype
Thrombopoiesis