Developing treatments to reduce noise-induced hearing loss and vestibular dysfunction

About This Grant

Significance to VA: Noise has long been known to induce hearing loss (noise-induced hearing loss - NIHL) however it can have a multisensory impact. Studies from our group and others now provide evidence that noise can also induce vestibular dysfunction (noise-induced vestibular dysfunction - NIVD) (Stewart et al., 2020a for review). NIHL reduces communication and ability to react to critical auditory information. NIVD reduces balance, gait and agility. Hearing and vestibular disorders affect millions of Americans and are among the most common service-related disabilities. There is greater hearing and vestibular loss for those who have been in service compared to the general population due to service-related noise exposures (Kerber et al., 2008). Long term NIHL and NIVD decrease quality of life, employment opportunity and contribute to dementia. Developing therapies will therefore hold significant relevance for Veterans as well as the general population. Innovation and Impact: Since noise has a multisensory impact, a single pharmacotherapeutic treatment that could be easily given prior to or shortly after noise to prevent/reduce or provide recovery from both NIHL and NIVD would be of great benefit. Identification and testing of such treatment is the goal of the proposed studies, using an animal model as a first step towards future clinical application. Rapamycin has shown promise by decreasing induction of markers for several underlying mechanisms of NIHL, oxidative / nitrative stress and inflammation, while reducing NIHL, when given intra peritoneal (Yuan et al., 2015). Our NIHL pilot studies showed that oral rapamycin is also effective, significantly decreasing NIHL from impulse noise. Our NIVD pilot study found that noise exposure that causes persistent NIVD induces the same markers of oxidative/ nitrative stress / inflammatory response in vestibular sensory epithelia, as found in cochlea with NIHL. We then found oral rapamycin prior to noise can reduce measures of NIVD. Our preliminary results, however, are from separate NIHL pilot studies in mice and NIVD pilot studies in rats. It is now necessary to confirm our pilot results and test if oral rapamycin treatment provides protection from both NIHL and NIVD using the same noise exposure condition in the same subjects. We also need to test efficacy for repeated noise exposures, common during service, and efficacy for treatment beginning shortly after noise. Specific Aims: (1) Test if rapamycin can prevent / reduce both NIHL and NIVD in the same subjects. (2) Test if rapamycin can prevent / reduce the enhancement of NIHL and NIVD from repeated noise exposure. (3) Test efficacy of starting rapamycin treatment of NIHL and NIVD 1 day or 3 days after noise. Methodology: The proposed studies will assess noise exposures that can be encountered during service, examining multisensory consequences on NIHL and NIVD. Studies will assess auditory brainstem response (ABR), distortion product otoacoustic emission (DPOAE), and vestibular shot-latency evoked potential (VsEP), changes in static head position and stability, and measure the tilt-maculo-ocular reflex (tMOR) before and after noise exposure. Motor consequences will be assessed with balance beam crossing metrics. Studies will use these metrics to determine the potential for rapamycin to prevent, reduce or induce recovery from NIHL and NIVD when administered prior to or shortly after noise exposure. Path to Translation/Implementation: This is a basic science proposal focusing on the characterization of noise-induced vestibular loss at levels that cannot be carried out with the control, precision, and range in human subjects that is possible in rats. As we characterize the efficacy of treatment on noise induced pathology and functional changes, our work will inform clinical measurements that can be tested with available or newly developed tools in the future. Rapamycin (sirolimus) is already given orally in clinical application for other disorders and could be re-purposed for treating NIHL and NIVD.