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(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，在美国每年影响795,000人，直接和间接造成386亿美元的损失。中风I是一种快速进行性疾病，在中风发作3小时后，大脑损伤几乎完全。对于减轻中风负担和改善中风患者预后的安全中风治疗，有一个重大的未得到满足的需求。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，这种药物可以在 甚至在到达医院之前(例如，由护理人员)，或在医院到达时立即进入社区，从而在第一个“黄金小时”内阻止中风的进展，最好是不晚于中风发病后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)，被称为“PSD95抑制物”。我们已经开发了一种原型(名为“NA-1”)，可以减少动物和人类的中风损害，但它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。我们的目标是对每种药物进行评估，以便在未来的临床试验中选择进一步开发的最佳候选药物。这将通过以下步骤完成：体外铅选择：将在体外评估这7个候选药物在动物中风模型中预测疗效和临床应用的最佳特性；在动物中选择LAD：将在大鼠身上评估相同的候选药物是否缺乏低血压，然后进行更详细的动物研究，包括对药物的疗效进行评估 实验性中风。最有效和最安全的单身候选人将晋级 下一步；生产和配方研究：主要的PSD95抑制剂将按照法规(FDA/ICH)标准生产，并用于在药物瓶中创建一种配方，以保护药物不被降解，并可用于救护车或医院；安全药理学和毒性测试。然后，这一主要候选药物将在必要的研究中进行测试，以证明在动物身上的安全性，并确认它适合推进IND的申请，进行第一阶段的人体试验。提交IND：该项目将最终向FDA提交IND，进行第一阶段的人体试验。我们已经成功地将NA-1从发现到成功的第二阶段人类临床试验，并在开发PSD95抑制剂和提交IND提交的过程中积累了经验。因此，我们相信，该项目将为进一步开发提供一种安全的紧急神经保护剂，以减轻中风对我们社会的特殊负担。