Development of Pirenzepine for HIV-SN

项目总结 全球超过3670万人艾滋病毒呈阳性，其中包括美国的120万人。与HIV相关的 感觉神经病(HIV-SN)是HIV最常见的神经系统表现，其特征是 远端对称性，主要为感觉性多发性神经病。HIV-SN可能代表临床上无法区分的两种 具有不同发病机制的神经病：感觉神经元相互作用引起的远端轴突变性 带有HIV相关蛋白，如gp120和tat，以及抗逆转录病毒疗法(Art)诱导的毒性 神经病变，ART也可能增强HIV蛋白诱导的HIV-SN。最近的研究表明， 线粒体功能障碍在HIV-SN发病机制中的作用及神经元线粒体生物发生障碍 质量控制(生物发生-有丝分裂轴)发生在HIV-SN患者中。目前还没有一种治疗方法 针对HIV-SN潜在的病理过程，但对线粒体作用的新认识 功能障碍的潜在发病机制提供了一种潜在的治疗方法。学院派创始人 Win SanTor的最近报道称，从外周感觉神经元长出的轴突处于胆碱能 1型M受体(M1R)介导的约束机制。刺激M1R抑制 线粒体功能，从而限制神经元的能量供应和轴突生长。相反，对M1R的抑制 激活AMP激活的蛋白激酶(AMPK)，从而增强线粒体的生物能量 功能与轴突再生。抑制M1R还可预防和逆转远端退行性变的指标 糖尿病和化疗所致神经病变动物模型中的神经病变。这些有希望的发现 提示M1R拮抗剂的治疗效果有可能扩展到不同的外周。 线粒体功能受损的神经病。我们最近发现，老鼠模型 过度表达艾滋病毒相关蛋白会出现线粒体功能障碍，并出现神经病变的症状。 此外， 在体外，暴露于HIV蛋白gp120的感觉神经元突起生长减少。 通过使用M1R拮抗剂哌仑西平预防，同时分娩引起的角膜神经丢失 Gp120对正常小鼠眼部的影响可通过同时局部应用 一台M1R 对抗者。基于这些结果，这个第一阶段STTR项目的目标是：1)评估哌仑西平的疗效 抗HIV-Tat蛋白表达的小鼠神经病变；2)评价哌仑西平治疗神经病变的疗效 在同时接受ART治疗的表达HIV-gp120蛋白的小鼠中。圆满完成这一阶段 该项目将支持匹伦西平作为治疗艾滋病毒的新疗法的进一步临床前开发。 序列号。在第二阶段，我们将进一步定义哌仑西平的安全性/毒理学概况，以支持IND的备案 向FDA提出申请。

PROJECT SUMMARY Over 36.7 million people worldwide, including 1.2 million people in the USA are HIV positive. HIV-associated sensory neuropathy (HIV-SN) is the most frequent neurological manifestation of HIV and is characterized as a distal symmetrical, predominantly sensory, polyneuropathy. HIV-SN may represent 2 clinically indistinguishable neuropathies with distinct pathogenesis: a distal axonal degeneration caused by interaction of sensory neurons with HIV-associated proteins such as gp120 and Tat and also an anti-retroviral therapy (ART)-induced toxic neuropathy, ART may also potentiate the HIV-SN induced by HIV proteins. Recent studies have implicated mitochondrial dysfunction in the pathogenesis of HIV-SN and disruption of neuronal mitochondrial biogenesis and quality control (biogenesis-mitophagy axis) occurs in HIV-SN patients. There is no current treatment that targets a pathological process underlying HIV-SN, but the emerging appreciation of the role of mitochondrial dysfunction in the underlying pathogenesis provides a potential therapeutic approach. The academic founders of WinSanTor recently reported that neurite outgrowth from peripheral sensory neurons is under a cholinergic constraint mechanism mediated by type 1 muscarinic receptors (M1R). Stimulation of the M1R restrains mitochondrial function, thereby limiting neuronal energy supply and neurite growth. Conversely, inhibition of M1R activates AMP-activated protein kinase (AMPK) with subsequent enhancement of mitochondrial bioenergetic function and neurite regeneration. M1R inhibition also prevents and reverses indices of distal degenerative neuropathy in animal models of diabetic and chemotherapy-induced neuropathy. These promising findings suggest that the therapeutic efficacy of M1R antagonists has the potential to extend across diverse peripheral neuropathies in which mitochondrial function is compromised. We have recently found that mouse models that overexpress HIV-associated proteins exhibit mitochondrial dysfunction and develop symptoms of neuropathy. Further, reduced neurite outgrowth from sensory neurons exposed to the HIV protein gp120 in vitro was prevented by treatment with the M1R antagonist pirenzepine, while loss of corneal nerves induced by delivery of gp120 to the eye of normal mice was both prevented and reversed by concurrent topical application of a M1R antagonist. Based on these results, the goal of this Phase I STTR project is to 1) evaluate efficacy of pirenzepine against neuropathy in mice expressing HIV-Tat protein; 2) evaluate efficacy of pirenzepine against neuropathy in mice expressing HIV-gp120 protein with concurrent ART therapy. Successful completion of this Phase I project will support further pre-clinical development of pirenzepine as a novel therapeutic for treatment of HIV- SN. In Phase II, we will further define the safety/toxicology profiles of pirenzepine to support filing of an IND application with the FDA.