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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41DC015411-01A1
Agency Tracking Number: R41DC015411
Amount: $269,999.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIDCD
Solicitation Number: PA15-270
Solicitation Year: 2015
Award Year: 2016
Award Start Date (Proposal Award Date): 2016-09-01
Award End Date (Contract End Date): 2018-08-31
Small Business Information
Research Triangle Park, NC 27709-0003
United States
DUNS: 829949275
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (919) 619-8296
Business Contact
Phone: (919) 619-8296
Research Institution

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

* Information listed above is at the time of submission. *

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