Translation of a Novel Stroke Drug Administration

描述(申请人提供)：中风是美国发病率的主要原因，每年影响超过60万人。目前唯一可用于治疗中风的治疗药物是tPA等溶栓剂，这些药物疗效有限，由于存在出血风险，因此不适合许多患者。一种有希望替代溶栓剂的药物是一类通过靶向NMDA受体来阻断谷氨酸介导的兴奋性毒性的药物。这些药物在中风动物模型中效果良好，但在临床试验中失败，最常见的原因是剂量低于有效范围时出现神经或心血管副作用。在一期研究计划中，Arbor Vita已经确定了一类作用于NMDA受体下游的抑制剂，称为PSD-95拮抗剂。这些抑制剂在不阻断NMDA受体的电或钙通道功能的情况下，对局灶性脑缺血的啮齿动物模型有效。领先的PSD-95抑制剂TatNR2B9c的临床前开发证明了令人印象深刻的中枢神经系统安全性，与传统的NMDA受体阻滞剂相比，这是一个重要的好处。此外，TatNR2B9c的长期毒性很小。然而，急性心血管副作用存在，剂量仅略高于预计对人类有效的剂量。这些效应是由细胞摄取所需的部分融合肽引起的，但与PSD-95的阻断没有直接关系。这项建议的重点是修饰融合肽的这一部分，在不损失效力或疗效的情况下克服心血管副作用。然后，将通过开展基本的临床前安全性和有效性研究来开发得到的改进的PSD-95抑制剂，从而导致随后的临床测试和最终的商业化。该建议的具体目的是：1)确认TatNR2B9c衍生物具有细胞渗透性，可与PSD-95有效结合，但不会引发心血管副作用；2)展示最有希望的药物在卒中大鼠永久性软膜血管阻塞(P3VO)模型中的疗效；3)通过进行狗心血管(CV)安全性研究来证实铅肽的安全性提高；4)根据STAIR(中风学术行业圆桌会议)的建议表征铅肽的神经保护功效；5)进行一整套临床前安全性和毒性研究，以便向美国食品和药物管理局提交成功的研究性新药申请。这项研究的完成将导致多肽疗法的临床开发，有可能彻底改变中风的治疗方法，从而解决大量未得到满足的医疗需求。与公众健康相关：目前还没有针对中风引起的脑损伤的已获批准的药物，只有能够帮助恢复受影响区域的血液流动的药物。目前的拨款旨在改进和推进针对Arbor Vita确定的一种新靶点的临床测试药物，该靶点可以在中风发生后使用，并极大地减少由此造成的脑损伤。

DESCRIPTION (provided by applicant): Stroke is a major cause of morbidity in the United States, affecting over 600,000 people annually. The only therapeutics currently available for the treatment of stroke are thrombolytic agents such as tPA, which have limited efficacy and are inappropriate for many patients due to risk of hemorrhage. One promising alternative to thrombolytics has been a class of agents that block glutamate-mediated excitotoxicity by targeting the NMDA receptor. These drugs have worked well in animal models of stroke but have failed in clinical trials, most often due to the appearance of neurological or cardiovascular side effects at dosages lower than the efficacious range. In a Phase I research program, Arbor Vita has identified a class of inhibitors that act downstream of NMDA receptors termed PSD-95 antagonists. These inhibitors are effective in rodent models of focal ischemia without blocking the electrical or calcium channel functions of the NMDA receptor. Preclinical development of the lead PSD-95 inhibitor, the fusion peptide TatNR2B9c, demonstrated impressive central nervous system safety, an important benefit versus traditional NMDA receptor blockers. Moreover, the long term toxicity of TatNR2B9c was minimal. Acute cardiovascular side effects were present, however, at doses only slightly higher than those predicted to be effective in humans. These effects were caused by a portion of the fusion peptide required for cellular uptake, but not involved directly in PSD-95 blockade. The focus of this proposal is to modify this portion of the fusion peptide, to overcome the cardiovascular side effects without a loss in potency or efficacy. The resulting improved PSD- 95 inhibitor would then be developed by carrying out essential preclinical safety and efficacy studies leading towards subsequent clinical testing and eventual commercialization. The Specific Aims of the proposal are: 1) identify TatNR2B9c derivatives that are cell permeable and bind PSD-95 potently, but do not trigger cardiovascular side effects, 2) demonstrate efficacy of the most promising drugs in the rat permanent pial vessel occlusion (P3VO) model of stroke, 3) confirm the improved safety of the lead peptides by conducting a dog cardiovascular (CV) safety study, 4) characterize the neuroprotective efficacy of the lead peptides as guided by the STAIR (Stroke Academic Industry Roundtable) recommendations, and 5) conduct the complete battery of preclinical safety and toxicity studies required to file a successful Investigational New Drug Application with the U.S. Food and Drug Administration. Completion of this research will lead to clinical development of a peptide therapeutic with the potential to revolutionize the treatment of stroke and thereby address a massive unmet medical need. PUBLIC HEALTH RELEVANCE: There are no approved drugs directed at protecting against the brain damage caused by stroke, only drugs which can help restore blood flow to the afflicted area. The present grant aims to improve and advance towards clinical testing drugs directed at a novel target identified by Arbor Vita that can be administered after a stroke occurs and greatly reduce the resulting brain damage.