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: 8722792
• 负责人: MICHAEL TYMIANSKI
• 金额: $ 57.33万
• 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/8722792
• 关键词: Acute; Address; Adverse effects; Affect; Alteplase; Ambulances; Animals; Antihypertensive Agents; Arteries; Biological; Biological Assay; Brain; Brain Injuries; Brain hemorrhage; Canis familiaris; Clinical; Clinical Trials; Communities; Data; Development; Direct Costs; Disease; Dose; Drug Formulations; Drug Targeting; Early treatment; Emergency Situation; Evaluation; FDA approved; Facilities and Administrative Costs; Future; Growth; Histology; Hospitals; Hour; Human; Hypotension; Image; In Vitro; Individual; Infarction; Intervention; Investigation; Ischemia; Ischemic Stroke; Lead; Macaca; Magnetic Resonance Imaging; 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; Protein Binding; 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; public health relevance; receptor binding; response; socioeconomics; 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。中风是导致死亡和残疾的主要原因，每年影响美国 795,000 人，直接和间接损失达 386 亿美元。 中风是一种快速进展的疾病，中风发作后 3 小时内脑损伤几乎完全。 对安全中风治疗以减轻中风负担并改善中风患者预后的重大需求尚未得到满足。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，该药物足够安全，可以为中风患者提供 甚至在到达医院之前（例如，由护理人员）或到达医院后立即向社区提供信息，从而在第一个“黄金小时”内阻止中风进展，最好不迟于中风发作后 3 小时。这将通过开发一种安全有效的药物来实现，该药物针对神经元突触后密度 95 蛋白 (PSD95)，称为“PSD95 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，以便选择最佳的主要候选者，以便在未来的临床试验中进一步开发。这将通过以下步骤完成： 体外先导药物选择：将在体外评估 7 种候选药物的最佳特性，以预测动物中风模型的疗效和临床实用性；动物中的小伙子选择：将在大鼠中评估相同的候选人是否没有低血压，然后进行更详细的动物研究，包括评估药物在 实验性的笔画。 最有效和最安全的单一候选人将被晋级 下一步； 制造和配方研究：主要的 PSD95 抑制剂将按照监管 (FDA/ICH) 标准进行制造，并用于在药瓶中创建配方，以防止药物降解，并可在救护车或医院中使用； 安全药理学和毒性测试。 然后，该主要候选药物将在必要的研究中进行测试，以证明其在动物中的安全性，并确认其适合提交 IND 申请进行一期人体试验。提交 IND：该项目将最终向 FDA 提交 IND 进行第一阶段人体试验。 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 PSD95 抑制剂和提交 IND 申请的过程中拥有丰富的经验。因此，我们相信该项目将为进一步开发提供安全的紧急神经保护剂，以减轻中风给我们社会带来的巨大负担。