PREVENTING ZINC-INDUCED NEURONAL DAMAGE

我们将开发一种安全有效的治疗锌神经毒性的方法，锌是人类神经损伤的主要原因。锌诱导的神经元损伤是在中风、缺血、癫痫发作和钝性创伤后发生的兴奋性毒性级联反应的核心组成部分。此外，我们有新的证据表明Zn2+在阿尔茨海默病中促进淀粉样斑块和神经原纤维缠结的形成。我们和其他人已经在几种动物模型中证明锌螯合可以减少和/或逆转这种神经元损伤。对于治疗药物设计，我们将利用我们的专利，“定制”（点突变）锌结合蛋白。将这些锌结合蛋白运输到大脑中，将利用抗体来对抗可以携带蛋白质通过血脑屏障的转细胞载体（例如OX-26）。这种方法将允许设计治疗性中枢神经系统“锌缓冲液”，维持安全、适当、生理水平的细胞外Zn2+，而不干扰细胞内锌。在第一阶段，我们将(I)筛选锌结合特性和神经保护效力的候选点突变蛋白，（ii）开发与运输抗体连接的附着化学，以及（iii）在阿尔茨海默样和兴奋性锌毒性模型的啮齿动物模型中测试有希望的线索。在II期，体内动物试验将继续进行FDA针对II期和III期的临床前试验。拟议的商业应用：头部/脑部损伤是50岁以下人群死亡的主要原因。中风、脑血管病和癫痫发作袭击了更多的受害者，而由于心力衰竭或外科手术引起的脑缺血则降临到另一群人身上。一种有效的神经保护药物，可以减少所有这些情况下对脑细胞的兴奋性毒性/缺血性损伤，将有巨大的市场。此外，一种调节大脑Zn2+的药物，如果确实能减缓阿尔茨海默病的病理进展，将会找到第二个市场。

We shall develop a safe, effective therapy against zinc neurotoxicity, a major cause of neuronal injury in man. Zinc-induced neuronal injury is emerging as a core component of the excitotoxic cascade occurring after stroke, ischemia, seizures, and blunt trauma. Moreover, we have new evidence that Zn2+ promotes formation of both amyloid plaques and neurofibrillary tangles in Alzheimer's disease. We and others have already shown that zinc chelation can reduce and/or reverse this neuronal injury in several animal models. For therapeutic drug design, we will capitalize on our proprietary, "custom-made" (point-mutated) zinc-binding proteins. Transport of these zinc-binding proteins into the brain will utilize antibodies against transcytotic carriers (e.g., OX-26) that can carry proteins through the blood-brain barrier. This approach will allow design of therapeutic CNS "zinc buffers" that maintain safe, appropriate, physiological levels of extracellular Zn2+ without perturbing intracellular zinc. In Phase I, we will (i) screen candidate point-mutated proteins for zinc- binding properties and neuroprotective potency, (ii) develop attachment chemistry for linking to transport antibodies, and (iii) test promising leads in rodent models of both Alzheimer-like and excitotoxic models of zinc toxicity. In Phase II, in vivo animal testing will continue with FDA preclinical trials targeted for Phase II-Phase III. PROPOSED COMMERCIAL APPLICATION: Head/brain injury is the leading cause of death among individuals under 50. Stroke, CVA, and seizures strike many more victims, and cerebral ischemia due to cardiac failure or surgical procedures befall yet another group. An effective neruoprotective drug that could reduce the excitotoxic/ischemic injury to brain cells in all of these conditions would have a frankly enormous market. Further, a drug for regulating cerebral Zn2+, if that indeed slows the advance of Alzheimer's pathology, would find yet a second market.