Development of Pirenzepine for CIPN

项目摘要 化疗引起的周围神经病变（CIPN）是一种使人衰弱的疾病， 患者接受化疗，并限制剂量和治疗持续时间。症状包括 感觉丧失至疼痛性神经病变，并伴有神经电生理和结构指标 损害美国临床肿瘤学会目前没有提出预防的建议。 或逆转CIPN，并且仅提供了缓解症状性疼痛的中度推荐。CIPN是 因此是一个主要的未解决的临床问题。WinSanTor的创始人发现了一种新的自我平衡 在外周神经元中通过调节线粒体能量供应抑制轴突生长的机制。 操纵这种内源性机制可以用来改善神经元的能量供应， 毒性或代谢应激，从而支持神经保护和从已建立的损伤中恢复。我们 最近报道，调节这种机制的关键神经元受体是毒蕈碱受体， 乙酰胆碱1型受体（M1 R）和M1 R拮抗剂增加神经元呼吸能力和驱动 神经突生长此外，体内研究表明，选择性M1 R拮抗剂哌仑西平， 它已在全球范围内用于治疗胃溃疡30多年，预防和/或逆转了多种 毒性和代谢性损伤啮齿动物模型中的神经病指数。鼓励初步研究 第一阶段STTR奖的支持表明，pirenzpine既可以防止和逆转的指数 在紫杉醇诱导的CIPN模型中， 紫杉醇的杀肿瘤特性。第二阶段STTR项目的目标是确定最佳的 哌仑西平对紫杉醇诱导的CIPN的治疗方案（目标1），以建立最广泛的市场 对于这种方法，通过将研究扩展到由三种不同的化疗药物诱导的CIPN（Aim 2）， 完成必要的IND使能研究，为临床试验（目标3）做准备， 哌仑西平作为CIPN的第一种同类疗法。

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.