Development of Pirenzepine for HIV-SN

哌仑西平治疗 HIV-SN 的开发

基本信息

批准号：
9464143
负责人：
Jerel Adam Fields
金额：
$ 46.64万
依托单位：
WINSANTOR, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-28 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9464143
关键词：
5&apos -AMP-activated protein kinase Afferent Neurons Animal Model Anti-Retroviral Agents Bioenergetics Biogenesis Clinical Cornea Data Development Didanosine Disease Distal Energy Supply Exhibits Eye Fiber Goals Growth HIV HIV Envelope Protein gp120 HIV Seropositivity HIV tat Protein Impairment In Vitro Mediating Mitochondria Modeling Mus Muscarinic Acetylcholine Receptor Natural regeneration Nerve Neurites Neurologic Symptoms Neurons Neuropathy Pathogenesis Pathologic Processes Patients Peripheral Peripheral Nervous System Diseases Phase Phenotype Pirenzepine Polyneuropathy Process Proteins Quality Control Receptor Inhibition Reporting Role Safety Sensory Small Business Technology Transfer Research Symptoms Therapeutic Topical application Toxicology Transgenic Mice Treatment Efficacy antiretroviral therapy axonal degeneration base chemotherapy induced neuropathy cholinergic clinical translation density diabetic early onset experience in vivo indexing insight mitochondrial dysfunction mouse model neurite growth neurotoxicity novel therapeutic intervention novel therapeutics overexpression preclinical development prevent protein expression receptor sensory neuropathy tat Protein

项目摘要

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.

项目概要全球有超过 3670 万人（其中美国有 120 万人）艾滋病毒呈阳性。 HIV相关的感觉神经病 (HIV-SN) 是 HIV 最常见的神经系统表现，其特点是远端对称性，主要是感觉性多发性神经病。 HIV-SN 可能代表 2 临床上无法区分的具有独特发病机制的神经病：由感觉神经元相互作用引起的远端轴突变性与 HIV 相关的蛋白质（例如 gp120 和 Tat）以及抗逆转录病毒治疗 (ART) 引起的毒性神经病变，ART 还可能增强 HIV 蛋白诱导的 HIV-SN。最近的研究表明 HIV-SN 发病机制中的线粒体功能障碍和神经元线粒体生物发生的破坏 HIV-SN 患者中发生质量控制（生物发生-线粒体自噬轴）。目前尚无治疗方法目标是 HIV-SN 的病理过程，但线粒体作用的新兴认识潜在发病机制的功能障碍提供了潜在的治疗方法。学术创始人 WinSanTor 最近报道称，外周感觉神经元的神经突生长处于胆碱能状态 1 型毒蕈碱受体 (M1R) 介导的约束机制。 M1R 的刺激抑制线粒体功能，从而限制神经元能量供应和神经突生长。相反，抑制 M1R 激活 AMP 激活蛋白激酶 (AMPK)，随后增强线粒体生物能功能和神经突再生。 M1R 抑制还可以预防和逆转远端退行性指标糖尿病和化疗引起的神经病变动物模型中的神经病变。这些有希望的发现表明 M1R 拮抗剂的治疗功效有可能扩展到不同的外周血管线粒体功能受损的神经病。我们最近发现小鼠模型过度表达 HIV 相关蛋白会表现出线粒体功能障碍并出现神经病症状。更远，体外暴露于 HIV 蛋白 gp120 的感觉神经元的神经突生长减少通过使用 M1R 拮抗剂哌仑西平治疗可以预防，而分娩引起的角膜神经损失通过同时局部应用 gp120 对正常小鼠眼睛的影响，可以预防和逆转一个M1R 对手。基于这些结果，第一阶段 STTR 项目的目标是 1) 评估哌仑西平的疗效对抗表达 HIV-Tat 蛋白的小鼠的神经病变； 2) 评估哌仑西平对抗神经病变的功效在同时进行 ART 治疗的表达 HIV-gp120 蛋白的小鼠中。第一阶段顺利完成该项目将支持哌仑西平作为治疗艾滋病毒的新型疗法的进一步临床前开发 SN。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 的申请向 FDA 提出申请。