Noise induced hearing loss (NIHL) is the most common occupational disease for which no clinically effective drug is available. Since NIHL involves oxidation-linked loss of sensory hair cells and auditory neurons in the cochlea, there is a need for potent and effective antioxidants that offer protection to these tissues. In preliminary studies we have observed that the orally administered multifunctional antioxidant HK-2 that uses the innovative therapeutic strategy of combining both metal attenuating properties with free radical scavenging activities into one molecule, provides promising preventive protection against NIHL in rats. This proposal seeks to confirm, clarify, and expand on this observation by conducting in vivo dose-response studies in rats to determine the optimal dose of HK-2 required for NIHL protection. Subsequently, intervention studies will be conducted to determine whether the optimal dose of HK-2 is only protective when administered prior to damaging noise exposure or whether protection can also be obtained through intervention when administered at the onset of damaging noise exposure or even hours after exposure. To clarify the mechanism of action of HK-2, in vitro studies will be conducted in which are exposed to reactive oxygen species (ROS) which include superoxide, hydrogen peroxide and hydroxyl radicals, as well as reactive nitrogen species (RNS) derived from nitric oxide. HK-2, its monofunctional analogs, and parent compound will be used to define the relative importance of metal chelation versus free radical scavenging activity, the importance of mitochondrial function protection in these cochlear cells in the treatment of NIHL, and to demonstrate that HK-2 can protect against different sources of oxidative stress. The data obtained will provide the basis for an SBIR Phase 2 application to fund the necessary preclinical and toxicological studies required for obtaining a FDA investigational new drug (IND) application to develop multifunctional antioxidants for the clinical treatment of NIHL. House Ear Institute-Organ of Corti 1 (HEI-OC1) cells

Public Health Relevance

Prevention and Intervention studies will be conducted in rats to demonstrate that orally administered multifunctional antioxidants that independently scavenge free radicals while also binding select transition metals that participate in hydroxyl radical formation can protect against noise induced hearing loss (NIHL). In addition, cultured House Ear Institute-Organ of Corti 1 (HEI-OC1) cells exposed to various reactive oxygen species (ROS) and reactive nitrogen species (RNS) will be used to determine the specific mechanisms of action of multifunctional antioxidants in their protection against NIHL

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
1R43DC016766-01
Application #
9460803
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Miller, Roger
Project Start
2018-01-01
Project End
2019-04-30
Budget Start
2018-01-01
Budget End
2019-04-30
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Therapeutic Vision, Inc.
Department
Type
DUNS #
140231478
City
Elkhorn
State
NE
Country
United States
Zip Code
68022