Neuroprotection in Stroke Drug Development

美国每年约有80万人患上急性中风。目前没有 可用于急性中风患者的神经保护剂，中风是第三大主要药物 死因是。中风幸存患者的康复费用超过40美元 在美国每年10亿美元。一种有效的神经保护药物没有被 到目前为止，尽管制药行业做出了密集的努力，但大多数药物 不要越过血脑屏障(BBB)。神经营养因子是一种潜在的大分子 神经保护剂，但这些也不能通过血脑屏障。目前的研究计划旨在合并 神经营养因子药物的发现和BBB药物靶向技术，使重组 神经营养素可以重新组成基因工程融合蛋白，使其能够转运 人体延迟静脉给药后体内通过血脑屏障的神经营养素。 这种药物将对静脉注射后的中风患者产生神经保护作用， 因为神经保护剂是专门为穿过血脑屏障而设计的。之前 工作已经产生了AGT-120，这是一种基因工程融合蛋白，其中 神经营养素变异体与靶向配体融合，进行受体介导的转运 在体内跨越血脑屏障。这种BBB运输载体之前已经被基因工程改造成 可以在人体内使用，而不会产生免疫反应。融合蛋白是一种双功能分子。 它不仅跨越血脑屏障，而且还与神经元上的特定神经营养素受体结合，以 引起神经元神经保护。拟议工作将做以下工作：(I) 在良好的实验室操作条件下的AGT-120的药理学/毒理学，(Ii)提交 FDA批准急性中风患者单次静脉注射AGT-120， (Iii)L-Ⅱ期临床试验，考察安全性、耐受性和药代动力学，并探索 急性卒中后5小时内静脉注射AGT-120的疗效。AGT-120是第一个大型 专为跨越人体血脑屏障而研制的神经保护分子 在静脉注射后。

Approximately 800,000 persons in the U.S. suffer an acute stroke each year. There presently is no neuroprotective agent that can be given to patients with acute stroke, and stroke is the third leading cause of death. The costs for rehabilitation of patients that survive a stroke is greater than $40 billion per year in the U.S. The reason that an effective neuroprotective drug has not been developed so far, despite intensive efforts in the pharmaceutical industry, is that most of the drugs do not cross the blood-brain barrier (BBB). Neurotrophins are potential large molecule neuroprotectives but these, too, do not cross the BBB. The present research plan aims at a merger of neurotrophin drug discovery and BBB drug targeting technology, so that a recombinant neurotrophin can be re-formulated as a genetically engineered fusion protein to enable transport of the neurotrophin through the BBB in vivo following delayed intravenous administration in humans. Such a drug will cause neuroprotection in stroke patients following intravenous administration, because the neuroprotective agent will have been specifically designed to cross the BBB. Prior work has produced AGT-120, which is a genetically engineered fusion protein wherein the neurotrophin variant is fused to a targeting ligand that undergoes receptor-mediated transport across the BBB in vivo. This BBB transport vector has been previously genetically engineered to enable use in humans without immunological reaction. The fusion protein is a bi-functional molecule that not only crosses the BBB, but also binds to the specific neurotrophin receptor on neurons to cause neuronal neuroprotection. The following will be done in the proposed work: (i) pharmacology/toxicology of AGT-120 under Good Laboratory Practise conditions, (ii)submission of an IND to the FDA for single intravenous administration of AGT-120 to patients with acute stroke, (iii) phase l-ll clinical trial to examine safety, tolerability, and pharmacokinetics, and to explore the efficacy of intravenous AGT-120 within 5 hours of an acute stroke. AGT-120 is the first large molecule neuroprotective that has been specifically formulated to cross the BBB in humans following intravenous administration.