NIM811 FOR THE TREATMENT OF ACUTE SPINAL CORD INJURY

描述（由申请人提供）：脊髓损伤（SCI）是一种破坏性事件，构成了一个重大的健康问题。目前，SCI的治疗还没有有效的治疗方法，促进功能恢复的策略显然是必要的。该UOI提案的目的是对NIM811（一种线粒体通透性转换（mPT）抑制剂）在急性SCI治疗中的应用进行IND支持的临床前研究。这种方法是基于基本的假设，即维持线粒体功能，限制正在进行的细胞死亡和功能障碍的关键过程，将促进SCI后功能的恢复。目前的实验研究和临床观察表明，环孢菌素A（CsA），抑制mPT和促进线粒体的稳定性，可以在治疗急性创伤性脑损伤，脊髓损伤，最近在急性心肌梗死后的再灌注损伤的治疗效益。然而，CsA具有高毒性特征，其免疫抑制特性使得难以将任何神经保护作用归因于mPT的抑制。因此，模拟CsA对mPT的细胞保护作用但表现出最小免疫抑制特性和较低细胞毒性的化合物具有高治疗潜力。NIM811（Novartis）是一种非免疫抑制性环孢菌素类似物，其在纳摩尔浓度下抑制mPT并表现出显著较低的毒性特征。该实验室的大量“概念验证”研究已经证明了NIM811对中度SCI实验大鼠模型的许多功能结果的体内功效。实验计划将通过使用重复给药范例（具体目标1）记录NIM811在中度和重度SCI模型中的功能功效来扩展这些先前的观察。药代动力学研究和线粒体功能测定将用于确定临床相关治疗时间窗（具体目标2）。然后将使用最有效的重复剂量和最佳治疗窗进行长期功能研究（特定目标3）。然后将与FDA举行IND前会议，以确定并进行（如有必要）任何额外的IND启动毒性研究（具体目标4）。这些目标的完成将最终导致IND申请的提交，以启动I期人体临床试验。 相关性：脊髓损伤（SCI）是一种破坏性事件，构成了一个主要的健康问题。仅在美国，每年约有12，000例新发病例，目前约有250，000人患有SCI。据估计，每个人一生的医疗保健相关费用约为100万美元。目前，对于SCI的治疗还不存在有效的治疗方法。这些实验性研究将侧重于测试一种非常有前途的药物，旨在使用早期干预方法促进康复。

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.