Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Blood. 2013 May 9;121(19):3825-9, S1-3. doi: 10.1182/blood-2013-02-486779. Epub 2013 Mar 20.
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.
严重缺乏血浆 ADAMTS13 活性可导致血栓性血小板减少性紫癜（TTP），这是一种危及生命的综合征，目前唯一有效的治疗方法是血浆置换。多达 5%的 TTP 病例是遗传性的，由 ADAMTS13 基因突变引起。在这里，我们报告了重组腺相关病毒血清型 8（AAV8）介导的表达一种截断的小鼠 ADAMTS13 变体（MDTCS）的功效和安全性，该变体在间隔区后截断，用于 TTP 的小鼠模型。给予 AAV8-hAAT-mdtcs 的剂量大于 2.6×10(11)vg/kg 体重可导致治疗水平的血浆 ADAMTS13 活性持续表达。截断的 ADAMTS13 变体的表达消除了循环中超大的血管性血友病因子多聚体，预防了由志贺毒素-2 触发的 Adamts13(-/-)易感小鼠的严重血小板减少症，并降低了死亡率。这些数据支持 AAV 载体介导的表达一种类似的截断 ADAMTS13 变体作为人类遗传性 TTP 的一种新的治疗方法。
