ERK1/2 Inhibition Alleviates Noise-Induced Hearing Loss While Tempering Down the Immune Response

Abstract

Noise-induced hearing loss (NIHL) is a major cause of hearing impairment, yet no FDA-approved drugs exist to prevent it. Targeting the mitogen activated protein kinase (MAPK) cellular pathway has emerged as a promising approach to attenuate NIHL. Tizaterkib is an orally bioavailable, highly specific ERK1/2 inhibitor, currently in Phase-1 anticancer clinical trials. Here, we tested tizaterkib’s efficacy against permanent NIHL in mice at doses equivalent to what humans are currently prescribed in clinical trials. The drug given orally 24 hours after noise exposure, protected an average of 20–25 dB SPL in three frequencies, in female and male mice, had a therapeutic window >50, and did not confer additional protection to KSR1 genetic knockout mice, showing the drug works through the MAPK pathway. Tizaterkib shielded from noise-induced cochlear synaptopathy, and a 3-day, twice daily, treatment with the drug was the optimal determined regimen. Importantly, tizaterkib was shown to decrease the number of CD45 and CD68 positive immune cells in the cochlea following noise exposure, which could be part of the protective mechanism of MAPK inhibition.

The Paper Explained:

Problem:

Hearing loss occurs in more than 10% of the world population with noise-induced hearing loss as one of the main causes, yet no FDA-approved drugs exist to prevent it. Hearing loss negatively impacts many aspects of individual’s daily life and hearing aids do not work for everyone; therefore, a treatment is desperately needed to prevent this highly common disorder.

Results:

We have shown that the drug tizaterkib, a highly-specific ERK1/2 inhibitor, protects mice from hearing loss when given orally before, and 24–48 hours after, moderate-to-high noise intensity levels. Protection was achieved with drug doses that are equivalent to the ones currently tested in humans for anticancer treatment, and no deleterious side effects were exhibited in the animals. The drug reduced nerve connectivity damage, and the mechanism of action was shown to be through the MAPK cellular pathway by taking advantage of a genetic knockout mouse model that has reduced activity of this specific pathway. Interestingly, we could show that while mice treated with noise alone had increased infiltrating immune cells in their cochleae for days after noise exposure, mice treated with tizaterkib and noise had reduced infiltrating immune cells in their cochleae to the low baselines levels measured in mice who were not exposed to noise.

Impact:

Our study provides evidence that targeting the MAPK pathway is a viable approach to mitigate noise-induced hearing loss. Tizaterkib is a promising preclinical compound that was shown to have a large therapeutic index in mice while offering up to 80% hearing protection. The immune response was tempered down with tizaterkib treatment, which supports regulating the immune response as a possible therapeutic strategy for reducing noise-induced hearing loss, and could be part of the mechanism by which ERK1/2 and MAPK inhibition confer hearing protection effects.

For More Information:

All data needed to evaluate the conclusions in the paper are present in the paper and/or Expanded View. Additional data related to this paper may be requested from the authors.