NIM811 FOR THE TREATMENT OF ACUTE SPINAL CORD INJURY

描述（由申请人提供）：脊髓损伤（SCI）是一种构成重大健康问题的毁灭性事件。目前，还没有有效的治疗脊髓损伤的方法，促进功能恢复的策略显然是必要的。该UOI提案的目的是开展使用NIM811(一种线粒体通透性转移抑制剂（mPT）治疗急性脊髓损伤的ind临床前研究。该方法基于以下假设：维持线粒体功能（限制细胞持续死亡和功能障碍的关键过程）将增强脊髓损伤后的功能恢复。目前的实验研究和临床观察表明，环孢素A （CsA）具有抑制mPT和促进线粒体稳定性的作用，可用于治疗急性创伤性脑损伤、脊髓损伤以及最近的急性心肌梗死后再灌注损伤。然而，CsA具有高毒性，其免疫抑制特性使得很难将其归因于抑制mPT的任何神经保护作用。因此，模拟CsA对mPT的细胞保护作用，但表现出最小的免疫抑制特性和较低的细胞毒性的化合物具有很高的治疗潜力。NIM811（诺华公司）是一种非免疫抑制性环孢素类似物，在纳摩尔浓度下抑制mPT，毒性显著降低。该实验室的大量“概念验证”研究已经在实验大鼠中度脊髓损伤模型中证明了NIM811对许多功能结果的体内功效。实验计划将通过重复给药范式记录NIM811在中重度脊髓损伤模型中的功能功效来扩展这些先前的观察结果（Specific Aim 1）。药代动力学研究和线粒体功能测定将用于确定临床相关的治疗时间窗（Specific Aim 2）。然后将使用最有效的重复剂量和最佳治疗窗口进行长期功能研究（Specific Aim 3）。随后将与FDA举行IND前会议，以确定并在必要时进行任何额外的IND毒性研究（Specific Aim 4）。这些目标的完成将最终提交IND申请，以启动I期人体临床试验。

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.