NIM811 FOR THE TREATMENT OF ACUTE SPINAL CORD INJURY

NIM811 用于治疗急性脊髓损伤

• 批准号: 7768241
• 负责人: JOE E SPRINGER
• 金额: $ 49.17万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7768241
• 关键词: Acute; Acute myocardial infarction; Biological Assay; Cell Death; Clinical; Clinical Trials; Cyclosporine; Cyclosporins; Dose; Drug Design; Drug Kinetics; Early treatment; Event; Exhibits; Functional disorder; Health; Healthcare; Human; Immunosuppressive Agents; Individual; Life; Measures; Mitochondria; Modeling; Permeability; Phase; Process; Property; Rattus; Recovery; Recovery of Function; Reperfusion Injury; Spinal cord injury; Testing; Therapeutic; Time; Tissues; Toxic effect; Traumatic Brain Injury; United States; analog; base; clinically relevant; cost; cytotoxicity; effective therapy; functional outcomes; improved; in vivo; inhibitor/antagonist; meetings; preclinical study; research study

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) is a devastating event that constitutes a major health issue. At the present time, no effective treatments exist for the treatment of SCI and strategies that promote functional recovery are clearly warranted. The objective of this UOI proposal is to conduct IND-enabling preclinical studies for the use of NIM811, an inhibitor of mitochondrial permeability transition (mPT), in the treatment of acute SCI. This approach is based on the underlying hypothesis that maintaining mitochondrial function, a critical process for limiting ongoing cell death and dysfunction, will enhance recovery of function following SCI. Current experimental studies and clinical observations suggest that the cyclosporin A (CsA), which inhibits mPT and promotes mitochondrial stability, can be of therapeutic benefit in the treatment of acute traumatic brain injury, spinal cord injury, and more recently in reperfusion injury following acute myocardial infarction. However, CsA has a high toxicity profile and its immunosuppressive properties make it difficult to attribute any neuroprotective effects on inhibition of mPT. Therefore, compounds that mimic the cytoprotective actions of CsA on mPT, but exhibit minimal immunosuppressive properties and lower cytotoxicity have high therapeutic potential. NIM811 (Novartis) is a non-immunosuppressive cyclosporin analog that inhibits mPT at nanomolar concentrations and exhibits a significantly lower toxicity profile. Substantial "proof-of-concept" studies from this lab have demonstrated in vivo efficacy of NIM811 on a number of functional outcomes using an experimental rat model of moderate SCI. The experimental plan will expand on these previous observations by documenting NIM811 functional efficacy in models of moderate and severe SCI using a repeated dosing paradigm (Specific Aim 1). Pharmacokinetic studies and assays of mitochondrial function will be used to identify a clinically relevant therapeutic time window (Specific Aim 2). Long-term functional studies will then be performed using the most effective repeated dose and optimal therapeutic window (Specific Aim 3). A pre-IND meeting will then be held with the FDA to identify and conduct, if necessary, any additional IND- enabling toxicity studies (Specific Aim 4). The completion of these Aims will culminate in the filing of an IND application in order to initiate a Phase I human clinical trial. RELEVANCE: Spinal cord injury (SCI) is a devastating event that constitutes a major health issue. In the United States alone, approximately 12,000 new cases occur each year and some 250,000 people are currently living with SCI. The lifetime health care-related costs per individual are estimated to be around $1,000,000. At the present time, no effective treatments exist for the treatment of SCI. These experimental studies will focus on testing a highly promising drug designed to promote recovery using an early intervention approach.

描述（由申请人提供）：脊髓损伤（SCI）是构成重大健康问题的毁灭性事件。目前，明确保证尚无有效的治疗SCI治疗和促进功能恢复的策略的治疗方法。该UOI建议的目的是为使用NIM811（线粒体通透性跃迁（MPT）的抑制剂NIM811）进行指定的临床前研究，以治疗急性SCI。这种方法基于这样的基本假设：维持线粒体功能，限制持续的细胞死亡和功能障碍的关键过程将增强SCI后功能的恢复。当前的实验研究和临床观察结果表明，抑制MPT并促进线粒体稳定性的环孢菌素A（CSA）在治疗急性创伤性脑损伤，脊髓损伤的治疗方面可能具有治疗益处梗塞。但是，CSA具有高毒性，其免疫抑制特性使得很难将任何神经保护作用归因于MPT抑制。因此，模仿CSA对MPT的细胞保护作用的化合物，但具有最小的免疫抑制特性和较低的细胞毒性具有高治疗潜力。 NIM811（Novartis）是一种非免疫抑制环孢菌素类似物，可在纳摩尔浓度下抑制MPT，并表现出明显较低的毒性特征。该实验室的大量“概念验证”研究证明了使用中度SCI的实验大鼠模型在许多功能结果上的体内功效。实验计划将通过使用重复给药范式记录中度和重度SCI模型中的NIM811功能疗效来扩展这些先前的观察结果（特定AIM 1）。药代动力学研究和线粒体功能的测定将用于识别临床相关的治疗时间窗口（特定目标2）。然后，将使用最有效的重复剂量和最佳治疗窗口（特定目标3）进行长期功能研究。然后，将与FDA举行预录会议，以确定和进行任何其他毒性研究（特定目的4）。这些目标的完成将在提交IND申请中最终达到最终，以便启动I期人类临床试验。 相关性：脊髓损伤（SCI）是构成重大健康问题的毁灭性事件。仅在美国，每年大约发生了大约12,000例新病例，目前约有25万人患有SCI。每人终身医疗相关的费用估计约为1,000,000美元。目前，尚无有效治疗SCI的治疗方法。这些实验研究将着重于测试一种高度有前途的药物，旨在使用早期干预方法促进恢复。