Development of Pirenzepine for CIPN

CIPN 哌仑西平的开发

• 批准号: 9680813
• 负责人: Andrew Mizisin
• 金额: $ 62.4万
• 依托单位: WINSANTOR, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-23 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9680813
• 关键词: Acetylcholine; Address; American Society of Clinical Oncology; Award; Behavioral; Biological Assay; Bortezomib; Breast; Cancer Patient; Chemotherapy-induced peripheral neuropathy; Clinical; Clinical Trials; Clinical Trials Design; Colorectal Cancer; Contracts; Data; Development; Diabetic Neuropathies; Dichloroacetate; Disease; Dose; Drug Exposure; Drug Interactions; Electrophysiology (science); Energy Supply; Fiber; Frequencies; Funding; Future; Gastric ulcer; Goals; Grant; Growth; Injury; Intervention; Investigation; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Metabolic; Metabolic stress; Miniature Swine; Mitochondria; Modeling; Multiple Myeloma; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Antagonists; Muscarinic M1 Receptor; Muscarinics; Nerve; Neurites; Neurons; Neuropathy; Oral; Ovarian; Paclitaxel; Pathogenesis; Pathogenicity; Patients; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phase; Pirenzepine; Preparation; Prevention; Property; Prostate; Publishing; Recommendation; Recovery; Regimen; Regulation; Reporting; Respiration; Rodent; Rodent Model; Route; Sensory; Series; Small Business Technology Transfer Research; Symptoms; Therapeutic; Time; Toxic effect; Treatment Protocols; axon growth; chemotherapeutic agent; chemotherapy; cholinergic; commercialization; data acquisition; effective therapy; experimental study; improved; in vivo; indexing; male; malignant breast neoplasm; mitochondrial dysfunction; mouse model; neuronal growth; neuroprotection; novel; optimal treatments; oxaliplatin; pain relief; painful neuropathy; phase 1 study; pre-clinical; preclinical study; prevent; programs; prophylactic; receptor; respiratory; subcutaneous; treatment duration; treatment strategy

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.

项目概要 化疗引起的周围神经病变 (CIPN) 是一种使人衰弱的疾病，70% 的癌症都会受到影响 接受化疗的患者，并限制治疗的剂量和持续时间。症状范围包括 感觉丧失导致疼痛性神经病，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建议 或逆转 CIPN，并且仅提供缓解症状疼痛的中等建议。 CIPN 是 因此，这是一个未得到满足的临床重大问题。 WinSanTor 的创始人发现了一种新颖的稳态 周围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。 可以利用这种内源机制的操纵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既定损伤中恢复。我们 最近报道调节这一机制的关键神经元受体是毒蕈碱 乙酰胆碱 1 型受体 (M1R) 和 M1R 拮抗剂可增加神经元呼吸能力和驱动力 神经突生长。此外，体内研究表明，选择性 M1R 拮抗剂哌仑西平， 已在世界范围内使用 30 多年来治疗胃溃疡，预防和/或逆转多种胃溃疡 毒性和代谢损伤啮齿动物模型中的神经病变指数。鼓励初步研究 由第一阶段 STTR 奖项的支持表明，哌仑西平既可以预防也可以逆转 紫杉醇诱导的 CIPN 模型中的神经性疼痛和退行性神经病，且不妨碍 紫杉醇的抗肿瘤特性。 STTR 第二阶段项目的目标是确定最佳 哌仑西平对抗紫杉醇诱导的 CIPN 的治疗方案（目标 1），建立最广阔的市场 通过将研究扩展到由三种不同化疗药物诱导的 CIPN（目标 2），以实现这种方法 完成必要的 IND 支持研究，为临床试验（目标 3）做准备，以推进进程 哌仑西平作为针对 CIPN 的首个同类疗法。