Targeted Paraoxonase Fusion Protein as a Neurotherapeutic for Nerve Gas Agents

描述(申请人提供)：平民面临暴露于有机磷(OP)等化学神经毒气毒剂的风险。这些化合物对周围神经系统(PNS)和中枢神经系统(CNS)都有影响。中枢神经系统受到影响是因为OP是脂溶性小分子，由于跨越血脑屏障(BBB)运输，容易穿透大脑。由于中枢神经系统的影响，那些暴露在化学神经毒剂中的人面临着永久性脑损伤的风险。需要一种具有以下特征的神经毒气解毒剂：(A)快速降解OP的能力，如OP水解酶；(B)穿越人体血脑屏障的能力，从而使CNS中的OP失活；这将使暴露于化学神经毒剂中的个体的永久性脑损伤降至最低。人血中最活跃的OP水解酶是对氧磷酶(PON)-1。但是，PON-1不会跨越BBB。利用该公司开发的血脑屏障融合蛋白技术，大分子疗法，如PON-1，现在可以通过人类血脑屏障输送。本研究项目将对一种新型的PON-1融合蛋白进行基因工程，这将是一种双功能分子。新的融合蛋白既具有高PON-1 OP水解酶活性，又能通过受体介导的转运跨越人血脑屏障。这将通过将人类PON-1融合到BBB分子特洛伊木马上来实现，该分子特洛伊木马通过BBB运输将附着的药物从血液中携带到大脑中。将对新的融合蛋白进行改造，以使BBB转运活性和PON-1 OP水解酶活性都得到保留。民用和军用人群暴露于有机磷(OP)等化学神经毒剂的风险很大。这些化合物对周围神经系统(PNS)和中枢神经系统(CNS)都有影响。中枢神经系统受到影响是因为OP是脂溶性小分子，由于跨越血脑屏障(BBB)运输，容易穿透大脑。目前的工作将从基因工程的角度设计一种新的OP水解酶融合蛋白，它能够通过受体介导的运输穿过人类的血脑屏障。

DESCRIPTION (provided by applicant): Civilian populations are at risk for exposure to chemical nerve gas agents such as organophosphates (OPs). These compounds affect both the peripheral nervous system (PNS) and the central nervous system (CNS). The CNS is affected because the OPs are lipid-soluble small molecules that easily penetrate the brain, owing to transport across the blood-brain barrier (BBB). Owing to the effects in the CNS, those individuals surviving exposure to chemical nerve gas agents are at risk for permanent brain damage. What is needed is a nerve gas antidote with the following characteristics: (a) ability to rapidly degrade the OP, such as an OP hydrolase; (b) ability to cross the human BBB, so that OPs in the CNS are inactivated; this will minimize the permanent brain damage in individuals that survive exposure to chemical nerve gas agents. The most active OP hydrolase in human blood is paraoxonase (PON)-1. However, PON-1 does not cross the BBB. The delivery of large molecule therapeutics, such as PON-1, across the human BBB is now possible with BBB fusion protein technology developed by the Company. The present research project will genetically engineer a novel PON-1 fusion protein, which will be a bi-functional molecule. The new fusion protein will both contain high PON-1 OP hydrolase activity and be able to cross the human BBB via receptor-mediated transport. This will be accomplished by fusing human PON-1 to a BBB molecular Trojan horse that carries attached drugs from blood into brain via transport across the BBB. The new fusion protein will be engineered so that both the BBB transport activity and the PON-1 OP hydrolase activity will be preserved. Civilian, and military, populations are at risk for exposure to chemical nerve gas agents such as organophosphates (OPs). These compounds affect both the peripheral nervous system (PNS) and the central nervous system (CNS). The CNS is affected because the OPs are lipid-soluble small molecules that easily penetrate the brain, owing to transport across the blood-brain barrier (BBB). The present work will genetically engineer a novel OP hydrolase fusion protein that is able to cross the BBB in humans by receptor-mediated transport.