Development of Pirenzepine for HIV SN

PROJECT SUMMARY Over million people worldwide including 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 clinically indistinguishable neuropathies with distinct pathogenesis a distal axonal degeneration caused by interaction of sensory neurons with HIV associated proteins such as gp 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 muscarinic receptors M R Stimulation of the M R restrains mitochondrial function thereby limiting neuronal energy supply and neurite growth Conversely inhibition of M R activates AMP activated protein kinase AMPK with subsequent enhancement of mitochondrial bioenergetic function and neurite regeneration M R 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 M R 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 gp in vitro was prevented by treatment with the M R antagonist pirenzepine while loss of corneal nerves induced by delivery of gp to the eye of normal mice was both prevented and reversed by concurrent topical application of a M R antagonist Based on these results the goal of this Phase I STTR project is to evaluate efficacy of pirenzepine against neuropathy in mice expressing HIV Tat protein evaluate efficacy of pirenzepine against neuropathy in mice expressing HIV gp 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 PROJECT NARRATIVE HIV associated sensory neuropathy HIV SN is the most frequent neurological manifestation of HIV disease and the available therapies are limited to minimizing discomfort rather than treating nerve damage WinSanTor is developing a novel therapeutic approach for HIV SN based on their discovery of a cholinergic mechanism that regulates cellular energy supply in sensory neurons and on the recent insights into the pathophysiological processes in HIV SN induced by HIV proteins and antiretroviral therapy ART