Targeted Paraoxonase Fusion Protein as a Neurotherapeutic for Nerve Gas Agents

描述（由申请人提供）：平民有接触化学神经毒气剂（如有机磷）的风险。这些化合物影响外周神经系统（PNS）和中枢神经系统（CNS）。中枢神经系统受到影响，因为OP是脂溶性小分子，由于穿过血脑屏障（BBB）运输，很容易穿透大脑。由于对中枢神经系统的影响，暴露于化学神经毒气剂的幸存者有永久性脑损伤的风险。所需要的是具有以下特征的神经毒气解毒剂：（a）能够快速降解OP，例如OP水解酶;（B）能够穿过人BB B，使得CNS中的OP失活;这将使暴露于化学神经毒气剂的个体中的永久性脑损伤最小化。人体血液中最活跃的OP水解酶是对氧磷酶（PON）-1。然而，PON-1不穿过BBB。现在，通过公司开发的BBB融合蛋白技术，可以将大分子治疗剂（如PON-1）输送到人BBB中。目前的研究项目将基因工程一种新的PON-1融合蛋白，这将是一个双功能分子。新的融合蛋白将既含有高PON-1 OP水解酶活性，又能够通过受体介导的转运穿过人血脑屏障。这将通过将人PON-1与BBB分子特洛伊木马融合来实现，所述分子特洛伊木马通过跨越BBB的运输将附着的药物从血液携带到大脑中。新的融合蛋白将被工程化，使得BBB转运活性和PON-1 OP水解酶活性都将被保留。平民和军人都有可能接触到化学神经毒气剂，如有机磷。这些化合物影响外周神经系统（PNS）和中枢神经系统（CNS）。中枢神经系统受到影响，因为OP是脂溶性小分子，由于穿过血脑屏障（BBB）运输，很容易穿透大脑。目前的工作将基因工程的一种新的OP水解酶融合蛋白，能够通过受体介导的运输在人类的血脑屏障。

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.