Drug Activation of HSF1 for Prevention of Noise-Induced Hearing Loss

PROJECT SUMMARY The studies proposed here address a significant health issue the high incidence of acquired deafness from noise overstimulation that can result from recreational and workplace related activities and from service in the military Through a robust academic pharma partnership between investigators at the Kresge Hearing Research Institute with long standing interests and expertise in approaches to protect hearing and Chaperone Therapeutics a pharmaceutical company with a focus on using chaperone based strategies to treat neurodegenerative disease we propose Phase I studies to investigate the use of small molecules to activate and sustain the endogenous heat shock stress response for protection against noise induced hearing loss Experimental activation of the classic stress response by up regulation of heat shock proteins Hsps has been very effective in protecting the inner ear from noise induced hearing loss in animal models However a major roadblock to clinical applicability is the lack of a safe effective method to induce the heat shock response in the inner ear in humans without harmful consequences We will exploit the recent development of molecules that activate HSF the transcription factor that is the master activator of the heat shock response An early compound HSF A efficiently activates the pre existing pool of HSF and results in up regulation of cell protective Hsp genes This HSF activation reduces the levels of protein damage cytotoxicity and apoptosis in cultured mouse and human cells and in fly models of neurodegenerative disease Our preliminary studies indicate that HSF A also induces target Hsp gene expression in the cochlea and is capable of partial protection of hearing sensitivity when delivered prior to noise overstimulation In this Phase I study we outline experiments to further evaluate HSF A along with two optimized compounds chemically derived from HSF A that have enhanced bioavailability characteristics In the pharmacokinetic pharmacodynamic and toxicity studies in mice proposed in Aim we will evaluate delivery and the dosing requirements of these HSF activating compounds for effective bioavailability to induce the heat shock response in the cochlea Using this delivery and dosing information in Aim we will directly evaluate the ability of these compounds to protect hearing from noise overstimulation These studies will take a critical step in moving a promising therapeutic approach towards clinical application Evidence of significant protection would provide justification for additional pre clinical animal trials evaluating the efficacy of these molecules in the auditory system and a route to clinical testing in humans An effective method to activate the heat shock response in the inner ear could provide protection from noise induced hearing loss for millions of people PROJECT NARRATIVE The proposed studies will investigate new pharmacological approaches to induce the heat shock response in the mouse cochlea to protect it from damage and subsequent hearing loss due to noise exposure Small molecule approaches to induction of this protective pathway will provide paths for clinical testing in humans to alleviate the significant health problem of noise induced hearing loss