Development of Pirenzepine for CIPN

项目总结 化疗引起的周围神经病变(CIPN)是一种使人衰弱的疾病，70%的癌症患者 患者接受化疗，并限制治疗剂量和持续时间。症状范围从 痛性神经病的感觉丧失并伴有神经电生理和结构指标 损坏。美国临床肿瘤学会目前还没有提出预防的建议。 或逆转CIPN，对症状性疼痛缓解只提供适度的建议。CIPN是 因此，这是一个尚未得到满足的主要临床问题。WinSanTor的创始人发现了一种新的动态平衡 外周神经元中通过调节线粒体能量供应来抑制轴突生长的机制。 对这种内源性机制的操纵可以被用来改善对正在经历 毒性或代谢应激，从而支持神经保护和从既定损伤中恢复。我们 最近报道，调节这一机制的关键神经受体是毒扁豆碱 乙酰胆碱1型受体(M1R)及其拮抗剂增加神经元呼吸能力和驱动 轴突生长。此外，体内研究表明，选择性M1R拮抗剂吡伦西平， 它在世界范围内已被用于治疗胃溃疡30多年，预防和/或逆转多发性 中毒性和代谢损伤啮齿动物模型的神经病变指数。鼓励进行初步研究 由一项第一阶段STTR奖支持的研究表明，吡仑平可预防和逆转 紫杉醇诱导的CIPN模型的神经病理性疼痛和退行性神经病 紫杉醇的杀瘤作用。该第二阶段STTR项目的目标是定义最优 哌仑西平抗紫杉醇诱导的CIPN治疗方案(目标1)，建立最广泛的市场 通过将研究扩展到由三种不同的化疗药物诱导的CIPN(目标2)和 完成必要的支持IND的研究，为临床试验做准备(目标3)，正在推进 哌仑西平作为治疗CIPN的一线药物。

PROJECT SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition that afflicts 70% of cancer patients undergoing chemotherapy and limits the dose and duration of treatment. Symptoms range from sensory loss to painful neuropathy and are accompanied by electrophysiological and structural indices of nerve damage. The American Society of Clinical Oncology currently makes no recommendations for the prevention or reversal of CIPN and provides only a moderate recommendation for symptomatic pain relief. CIPN is therefore a major unmet clinical concern. WinSanTor's founders have discovered a novel homeostatic mechanism in peripheral neurons that restrains axonal growth via regulation of mitochondrial energy supply. Manipulation of this endogenous mechanism can be exploited to improve energy supply to neurons undergoing toxic or metabolic stress, thereby supporting both neuroprotection and recovery from established injury. We have recently reported that the key neuronal receptor regulating this mechanism is the muscarinic acetylcholine type 1 receptor (M1R) and that M1R antagonists increase neuronal respiratory capacity and drive neurite outgrowth. Additionally, in vivo studies demonstrated that the selective M1R antagonist pirenzepine, which has been used worldwide for 30+ years to treat gastric ulcers, prevented and/or reversed multiple indices of neuropathy in rodent models of toxic and metabolic injury. Encouraging preliminary studies supported by a Phase I STTR award demonstrate that pirenzpine both prevents and reverses indices of neuropathic pain and degenerative neuropathy in models of paclitaxel-induced CIPN without impeding the tumoricidal properties of paclitaxel. The goals of this Phase II STTR project are to define the optimal therapeutic regimen for pirenzepine against paclitaxel-induced CIPN (Aim 1), to establish the broadest market for this approach by extending studies to CIPN induced by three distinct chemotherapeutics (Aim 2) and to complete necessary IND-enabling studies in preparation for clinical trials (Aim 3) en route to advancing pirenzepine as a first in-class therapy against CIPN.