title: AAV-mediated expression of an ADAMTS13 variant prevents shigatoxin-induced thrombotic thrombocytopenic purpura.
abstract: Severe deficiency of plasma ADAMTS13 activity causes thrombotic thrombocytopenic purpura (TTP), a life-threatening syndrome for which plasma is the only effective therapy currently available. As much as 5% of TTP cases are hereditary, resulting from mutations of the ADAMTS13 gene. Here, we report the efficacy and safety of recombinant adeno-associated virus serotype 8 (AAV8)-mediated expression of a murine ADAMTS13 variant (MDTCS), truncated after the spacer domain, in a murine model of TTP. Administration of AAV8-hAAT-mdtcs at doses greater than 2.6 × 10(11) vg/kg body weight resulted in sustained expression of plasma ADAMTS13 activity at therapeutic levels. Expression of the truncated ADAMTS13 variant eliminated circulating ultralarge von Willebrand factor multimers, prevented severe thrombocytopenia, and reduced mortality in Adamts13(-/-) disease-prone mice triggered by shigatoxin-2. These data support AAV vector-mediated expression of a comparable truncated ADAMTS13 variant as a novel therapeutic approach for hereditary TTP in humans.
authors.affiliation: Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Sheng-Yu
authors.initials: SY
authors.lastname: Jin
authors.forename: Juan
authors.initials: J
authors.lastname: Xiao
authors.forename: Jialing
authors.initials: J
authors.lastname: Bao
authors.forename: Shangzhen
authors.initials: S
authors.lastname: Zhou
authors.forename: J Fraser
authors.initials: JF
authors.lastname: Wright
authors.forename: X Long
authors.initials: XL
authors.lastname: Zheng
mesh_terms: D000071120:ADAMTS13 Protein; D000818:Animals; D018389:Codon, Nonsense / Q000502:physiology; D019610:Cytoprotection / Q000235:genetics*; D000229:Dependovirus; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D008666:Metalloendopeptidases / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D011697:Purpura, Thrombotic Thrombocytopenic / Q000139:chemically induced / Q000517:prevention & control*; D022641:Shiga Toxin 2 / Q000633:toxicity*; D014170:Transformation, Genetic
chemical_list: D018389:Codon, Nonsense; D022641:Shiga Toxin 2; C502939:ADAMTS13 protein, mouse; D008666:Metalloendopeptidases; D000071120:ADAMTS13 Protein