Development of a next-generation PSD95 Inhibitor for the treatment of acute ische

开发用于治疗急性缺血的下一代 PSD95 抑制剂

• 批准号: 9128082
• 负责人: MICHAEL TYMIANSKI
• 金额: $ 119.89万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9128082
• 关键词: Acute; Address; Adverse effects; Affect; Alteplase; Ambulances; Animals; Antihypertensive Agents; Arteries; Binding Proteins; Biological; Biological Assay; Brain; Brain Injuries; Brain hemorrhage; Canis familiaris; Clinical; Clinical Trials; Communities; Data; Development; Diffusion Magnetic Resonance Imaging; Direct Costs; Disease; Dose; Drug Targeting; Early treatment; Emergency Situation; Evaluation; FDA approved; Facilities and Administrative Costs; Formulation; Future; Growth; Health; Histology; Hospitals; Hour; Human; Hypotension; Image; In Vitro; Individual; Infarction; Intervention; Investigation; Ischemia; Ischemic Stroke; Lead; Macaca; Middle Cerebral Artery Occlusion; Mission; Modeling; National Institute of Neurological Disorders and Stroke; Nature; Neurons; Neuroprotective Agents; Outcome; Paramedical Personnel; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Plasma; Primates; Process; Property; Proteins; Rattus; Reperfusion Therapy; Safety; Societies; Stroke; Testing; Therapeutic; Therapeutic Index; Time; Toxicity Tests; Translating; Vial device; base; brain tissue; disability; drug efficacy; experience; improved; in vivo; inhibitor/antagonist; mortality; nervous system disorder; neuroprotection; next generation; novel; preclinical safety; presynaptic density protein 95; prevent; protein protein interaction; prototype; receptor binding; response; socioeconomics; stroke treatment; thrombolysis; uptake

DESCRIPTION (provided by applicant): The mission of NINDS is to reduce the burden of neurological disease. Stroke is a leading cause of mortality and disability, affecting 795,000 people annually in the US at a direct and indirect cost of $38.6 billion. Stroke i a rapidly progressive disorder, with brain damage being near complete by 3 hours after stroke onset. There is a major unmet need for safe stroke treatments to reduce the burden of stroke and improve stroke victims' outcomes. We will address this need by developing an emergency stroke medication that is safe enough to be given to stroke victims in the community even before arrival to a hospital (e.g., by paramedic), or immediately on hospital arrival, thus arresting stroke progression within the first "golden hour" and preferaby no later than 3h after stroke onset. This will be achieved by developing a safe and effective drug that targets neuronal postsynaptic density 95 protein (PSD95), termed a "PSD95 inhibitor". We have already developed a prototype (termed "NA-1") that reduces stroke damage in animals and humans, but that has the side effect of producing hypotension. This makes NA-1 unsuitable for use in emergency situations. To improve on NA-1 we identified 7 potential related candidates. Our objective is to evaluate each in order to select the optimal Lead Candidate for further development in future clinical trials. This will be done through the followin steps: In vitro lead selection: The 7 candidates will be evaluated in vitro for optimal properties that are predictive of efficacy in animal stroke models and for clinical utility; Lad selection in animals: The same candidates will be evaluated in rats for lack of hypotension and then advanced to more detailed animal studies that include evaluations of the drugs' efficacy in experimental strokes. The most effective and safe single candidate will be advanced to the next steps; Manufacturing and formulation studies: The lead PSD95 inhibitor will be manufactured to regulatory (FDA/ICH) standards and used to create a formulation in a drug vial that protects the drug from degrading and that can be used in an ambulance or a hospital; Safety Pharmacology and Toxicity testing. This lead candidate will then be tested in the necessary studies to demonstrate safety in animals, and to confirm that it is appropriate for advancement to a filing of an IND for a Phase 1 human trial. Filing of an IND: The project will culminate with a filing of an IND with the FDA for a Phase 1 human trial. We have already successfully translated NA-1 all the way from its discovery to a successfl phase 2 human clinical trial and are experienced in the process of developing a PSD95 inhibitor and the filing of IND submissions. We are thus confident that this project will provide a safe emergency neuroprotectant for further development in order to reduce the extraordinary burden of stroke on our society.

描述（由申请人提供）：NINDS的使命是减轻神经系统疾病的负担。中风是死亡和残疾的主要原因，在美国每年影响795，000人，直接和间接成本为386亿美元。 中风是一种快速进行性疾病，在中风发作后3小时，脑损伤接近完全。 安全的中风治疗以减轻中风负担和改善中风患者的结果存在重大未满足的需求。我们将通过开发一种足够安全的紧急中风药物来满足这一需求， 社区甚至在到达医院之前（例如， 通过护理人员），或在到达医院时立即进行，从而在第一个“黄金小时”内并且优选地不晚于中风发作后3小时阻止中风进展。这将通过开发一种安全有效的靶向神经元突触后密度95蛋白（PSD 95）的药物来实现，称为“PSD 95抑制剂”。我们已经开发出一种原型（称为“NA-1”），可以减少动物和人类的中风损伤，但具有产生低血压的副作用。这使得NA-1不适合在紧急情况下使用。为了改进NA-1，我们确定了7个潜在的相关候选者。 我们的目标是评估每一个，以选择最佳的候选铅在未来的临床试验中进一步发展。这将通过以下步骤完成：体外电极导线选择：将在体外评价7种候选电极导线的最佳特性，这些特性可预测动物卒中模型中的疗效和临床实用性;动物中的电极导线选择：将在大鼠中评价相同的候选物是否缺乏低血压，然后进行更详细的动物研究，包括评价药物疗效 实验性中风 最有效和最安全的单个候选人将被推进到 下一步;生产和制剂研究：将按照监管（FDA/ICH）标准生产先导PSD 95抑制剂，并用于在药瓶中制备制剂，以保护药物免于降解，并可用于救护车或医院;安全性药理学和毒性试验。 然后，将在必要的研究中对该先导候选药物进行检测，以证明其在动物中的安全性，并确认其适合于提交IND用于1期人体试验。IND申请：该项目最终将向FDA提交IND申请，用于1期人体试验。 我们已经成功地将NA-1从发现到成功的2期人体临床试验，并且在开发PSD 95抑制剂和提交IND申请的过程中经验丰富。因此，我们有信心，该项目将提供一种安全的紧急神经保护剂，以进一步发展，以减少中风对我们社会的巨大负担。