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.

项目总结