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）：NIND的使命是减轻神经系统疾病的负担。中风是死亡率和残疾的主要原因，每年在美国的795,000人以386亿美元的直接和间接成本影响。 中风I迅速进行性疾病，脑损伤在中风发作后3小时接近完成。 需要安全的中风治疗以减轻中风的负担并改善中风受害者的结果，这是一个很大的未满足。我们将通过开发一种紧急中风药物来满足这种需求，该药物足够安全，可以在 社区甚至在到达医院之前（例如，由医护人员）或医院到达后立即到达，从而在第一个“黄金时光”中逮捕了中风的进展，并在中风发作后不迟于3H。这将通过开发针对神经元突触后密度95蛋白（PSD95）的安全有效药物来实现，该药物称为“ PSD95抑制剂”。我们已经开发了一种原型（称为“ NA-1”），可减少动物和人类的中风损害，但这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。为了改善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个人，以便在未来的临床试验中选择最佳的铅候选者进行进一步发展。这将通过以下步骤进行：体外铅选择：将在体外评估7个候选物，以预测动物中风模型和临床实用性的最佳特性；在动物中选择的LAD：将在大鼠中评估相同的候选者，因为缺乏低血压，然后升级到更详细的动物研究，其中包括对药物的功效评估 实验中风。 最有效，最安全的单一候选人将被提升到 下一步； 制造和配方研究：铅PSD95抑制剂将用于监管（FDA/ICH）标准，并用于在药瓶中创建一种制剂，以保护该药物免受降解，可用于救护车或医院； 安全药理学和毒性测试。 然后，将在必要的研究中对该主要候选人进行测试，以证明动物的安全性，并确认该候选人适合提高1阶段人类试验的IND。 IND的备案：该项目将通过向FDA提交IND的1阶段人类试验。 我们已经成功地将NA-1从其发现转换为SuccessFL 2阶段人类临床试验，并且在开发PSD95抑制剂和提交IND提交的过程中经验丰富。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，以进一步开发，以减轻我们社会中风的特殊负担。