title: Correction of murine ADAMTS13 deficiency by hematopoietic progenitor cell-mediated gene therapy.
abstract: 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.
authors.affiliation: Department of General Surgery, The Children's Hospital of Philadelphia and The University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Laje
authors.forename: Dezhi
authors.initials: D
authors.lastname: Shang
authors.forename: Wenjing
authors.initials: W
authors.lastname: Cao
authors.forename: Masami
authors.initials: M
authors.lastname: Niiya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Endo
authors.forename: Antoneta
authors.initials: A
authors.lastname: Radu
authors.forename: Nicole
authors.initials: N
authors.lastname: DeRogatis
authors.forename: Friedrich
authors.initials: F
authors.lastname: Scheiflinger
authors.forename: Philip W
authors.initials: PW
authors.lastname: Zoltick
authors.forename: Alan W
authors.initials: AW
authors.lastname: Flake
authors.forename: X Long
authors.initials: XL
authors.lastname: Zheng
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency* / Q000235:genetics; D000071120:ADAMTS13 Protein; D000818:Animals; D015153:Blotting, Western; D002341:Carotid Artery Thrombosis / Q000517:prevention & control; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007150:Immunohistochemistry; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016133:Polymerase Chain Reaction; D011697:Purpura, Thrombotic Thrombocytopenic / Q000235:genetics / Q000628:therapy*; D014161:Transduction, Genetic; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human