Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice
Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice
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DOI：
10.1126/scitranslmed.aay0356
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发表时间：
2020-01-22
影响因子：
17.1
通讯作者：
Chilukuri, Nageswararao
中科院分区：
文献类型：
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作者：
Betapudi, Venkaiah;Goswami, Reena;Chilukuri, Nageswararao
化学战神经毒剂是一种有机磷化合物，会引发胆碱能危机，几乎没有时间进行医疗干预来预防死亡。目前的化学治疗方案可以预防死亡，但不能预防暴露后并发症，例如脑损伤和永久性行为异常。在本研究中，我们展示了一种腺相关病毒8（AAV8）介导的对氧磷酶1变体IF-11（PON1-IF11）基因疗法，可为小鼠提供无症状预防性保护，使其免受多种致死剂量的G型化学战神经毒剂（即塔崩、沙林、环沙林和索曼）的影响长达5个月。单次注射负载PON1-IF11基因的肝脏特异性腺相关病毒颗粒，即可表达和分泌毫克量的重组PON1-IF11，其具有在啮齿动物体外和体内将G型化学战神经毒剂分解为生物非活性产物的催化能力。根据血液学参数和血清化学特征判断，血液中含有毫克浓度的重组 PON1-IF11 的小鼠没有表现出临床毒性症状。我们的研究揭示了开发一次性应用基因疗法的途径，以表达一种近乎天然的循环治疗性 PON1-IF11 蛋白，该蛋白有可能在数周至数月内保护人类免受 G 型化学战神经毒剂的侵害。
Chemical warfare nerve agents are organophosphorus chemical compounds that induce cholinergic crisis, leaving little or no time for medical intervention to prevent death. The current chemical treatment regimen may prevent death but does not prevent postexposure complications such as brain damage and permanent behavioral abnormalities. In the present study, we have demonstrated an adeno-associated virus 8 (AAV8)-mediated paraoxonase 1 variant IF-11 (PON1-IF11) gene therapy that offers asymptomatic prophylactic protection to mice against multiple lethal doses of G-type chemical warfare nerve agents, namely, tabun, sarin, cyclosarin, and soman, for up to 5 months in mice. A single injection of liver-specific adeno-associated viral particles loaded with PON1-IF11 gene resulted in expression and secretion of recombinant PON1-IF11 in milligram quantities, which has the catalytic power to break down G-type chemical warfare nerve agents into biologically inactive products in vitro and in vivo in rodents. Mice containing milligram concentrations of recombinant PON1-IF11 in their blood displayed no clinical signs of toxicity, as judged by their hematological parameters and serum chemistry profiles. Our study unfolds avenues to develop a one-time application of gene therapy to express a near-natural and circulating therapeutic PON1-IF11 protein that can potentially protect humans against G-type chemical warfare nerve agents for several weeks to months.