Development of Pirenzepine for HIV-SN

哌仑西平治疗 HIV-SN 的开发

• 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
• 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' -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

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.

项目摘要 全世界有超过3670万人，包括美国的120万人是艾滋病毒阳性。hiv相关 感觉神经病（HIV-SN）是HIV最常见的神经学表现，其特征在于 远端对称，主要是感觉，多发性神经病。HIV-SN可能代表2种临床上难以区分的 具有不同发病机制的神经病：由感觉神经元相互作用引起的远端轴突变性 与HIV相关蛋白如gp 120和达特，以及抗逆转录病毒疗法（ART）诱导的毒性 ART还可增强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合成的破坏 和质量控制（生物发生-线粒体自噬轴）发生在HIV-SN患者中。目前没有任何治疗方法， 靶向HIV-SN的病理过程，但对线粒体作用的新认识， 潜在发病机制中的功能障碍提供了一种潜在的治疗方法。学术创始人 WinSanTor的最近报道，来自外周感觉神经元的神经突生长是在胆碱能作用下进行的。 1型毒蕈碱受体（M1 R）介导的限制机制。M1 R抑制的刺激 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M1 R 激活AMP激活蛋白激酶（AMPK），随后增强线粒体生物能量 功能和神经突再生。M1 R抑制还可预防和逆转远端退行性变的指数。 在糖尿病和化疗诱导的神经病变的动物模型中，这些有希望的发现 这表明M1 R拮抗剂的治疗功效有可能扩展到不同的外周血。 线粒体功能受损的神经病。我们最近发现， 过表达HIV相关蛋白表现出线粒体功能障碍并出现神经病症状。 此外，本发明还 体外暴露于HIV蛋白gp 120的感觉神经元的轴突生长减少， 用M1 R拮抗剂哌仑西平治疗可以预防，而分娩引起的角膜神经丧失 通过同时局部应用 a M1R 拮抗剂基于这些结果，该I期STTR项目的目标是：1）评价哌仑西平的疗效 抗神经病变的小鼠表达HIV-Tat蛋白; 2）评价哌仑西平抗神经病变的功效 在表达HIV-gp 120蛋白的小鼠中同时进行ART治疗。成功完成第一阶段 该项目将支持哌仑西平作为一种治疗艾滋病毒的新型治疗药物的进一步临床前开发， SN.在第二阶段，我们将进一步确定哌仑西平的安全性/毒理学特征，以支持IND申请 向FDA申请。