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 Blood, 5 March 2009, Vol. 113, No. 10, pp. 2172-2180.
Prepublished online as a Blood First Edition Paper on January 13, 2009; DOI 10.1182/blood-2008-08-173021.

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GENE THERAPY

Correction of murine ADAMTS13 deficiency by hematopoietic progenitor cell–mediated gene therapy

Pablo Laje1,*, Dezhi Shang2,*, Wenjing Cao2, Masami Niiya2, Masayuki Endo1, Antoneta Radu1, Nicole DeRogatis2, Friedrich Scheiflinger3, Philip W. Zoltick1, Alan W. Flake1, and X. Long Zheng2

Departments of 1 General Surgery and 2 Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania Medical Center, Philadelphia; and 3 Baxter Innovations GmbH, Discovery Research, Vienna, Austria

ADAMTS13, a metalloprotease primarily synthesized in liver and endothelial cells, cleaves von Willebrand factor (VWF) at the central A2 domain, thereby reducing the sizes of circulating VWF multimers. Genetic or acquired deficiency of plasma ADAMTS13 activity leads to a potentially fatal syndrome, thrombotic thrombocytopenic purpura (TTP). To date, plasma infusion or exchange is the only proven effective therapy for TTP. In search for a better therapy, an autologous transplantation of hematopoietic progenitor cells transduced ex vivo with a self-inactivating lentiviral vector encoding a full-length murine Adamts13 and an enhanced green fluorescent protein (GFP) reporter gene was performed in Adamts13–/– mice after irradiation. All recipient mice showed detectable ADAMTS13 antigen and proteolytic activity in plasma despite only low levels of bone marrow chimerism. The levels of plasma ADAMTS13 were sufficient to eliminate the ultralarge VWF multimers and offered systemic protection against ferric chloride–induced arterial thrombosis. The data suggest that hematopoietic progenitor cells can be genetically modified ex vivo and transplanted in an autologous model to provide adequate levels of functional ADAMTS13 metalloprotease. This success may provide the basis for development of a novel therapeutic strategy to cure hereditary TTP in humans.


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