September 4, 2024

Therapeutic Candidates for Hearing Loss

Hearing loss affects up to 10% of people worldwide and therapeutic interventions are desperately needed. Noise exposure and chemotherapy treatments are leading causes of this impairment, but currently there is only one FDA-approved drug for a subgroup of cisplatin-treated cancer patients. Hearing loss is caused by damage to inner ear cell types as the outer hair cells and synaptic dysfunction. Drug repurposing is a strategy for addressing unmet medical needs that can be quicker and more cost-effective than traditional drug development.

Three recent papers by Tal Teitz’s research group examined the top drug candidates tizaterkib, trametinib, and oseltamivir phosphate (brand name Tamiflu) that came up in unbiased cell-based screens of ~5,500 FDA-approved drugs and bioactive compounds for protection against cisplatin-induced cell death. The drugs were tested in mouse cochlear explants and in established cisplatin- and noise-induced hearing loss animal models. Drug treatments in the animal models were done by oral delivery, and minimum in vivo effective doses were determined for protection against cisplatin- or noise-induced auditory brain stem response (ABR) threshold shifts, outer hair cell loss, and cochlear synaptopathy.  

Tizaterkib, a phase-1 clinical anticancer ERK1/2 inhibitor, in the mitogen-activated protein kinase (MAPK) pathway, was found to be protective against noise-induced hearing loss (Lutze et al., 2024, International Journal of Molecular Sciences, ERK1/2 Inhibition via the Oral Administration of Tizaterkib Alleviates Noise-Induced Hearing Loss While Tempering down the Immune Response). Importantly, tizaterkib was shown to decrease the number of CD45- and CD68-positive immune cells in the mouse cochlea following noise exposure. This study suggests that repurposing tizaterkib and the ERK1/2 kinases’ inhibition could be a promising strategy for the treatment of noise-induced hearing loss.

Trametinib, an anticancer FDA-approved drug MEK1/2 inhibitor, in the MAPK pathway as well, was examined for cisplatin- and noise-induced hearing loss (Lutze et al., 2024 Pharmaceuticals, Trametinib, a MEK1/2 Inhibitor, Protects Mice from Cisplatin- and Noise-Induced Hearing Loss). Trametinib protected against cisplatin-induced hearing loss in a translationally relevant mouse model and did not interfere with cisplatin’s tumor-killing efficacy in cancer cell lines. Higher doses of trametinib were toxic to mice when combined with cisplatin, but lower doses of the drug were protective against hearing loss without any known toxicity. Trametinib also protected mice from noise-induced hearing loss and synaptic damage. Dabrafenib, a BRAF inhibitor and FDA-approved drug had a better therapeutic index in animals by this study and previous studies from the Teitz lab (Ingersoll et al, Science Advances, 2000; Ingersoll and Lutze, JCI Insight, 2023; Ingersoll et al, J. of Neuroscience, 2024). This study shows that MEK1/2 inhibition protects against both insults of hearing loss, as well as that targeting all three kinases in the MAPK pathway (BRAF, MEK1/2 and ERK1/2) protects mice from cisplatin- and noise-induced hearing loss.  

Oseltamivir, a widely used antiviral drug with a good safety profile, was investigated in the Longsworth et al, Clinical and Translational Medicine, 2024 paper (accepted for publication July 25th, 2024: preprint in bioRxiv Oseltamivir (Tamiflu), a Commonly Prescribed Antiviral Drug, Mitigates Hearing Loss in Mice).  Oseltamivir treatment reduced in mice outer hair cells death after cisplatin treatment and mitigated cochlear synaptopathy after noise exposure. A potential binding protein, ERK1/2, associated with inflammation, was shown to be activated with cisplatin treatment and reduced by oseltamivir cotreatment in cochlear explants. As observed for Tizaterkib, the number of infiltrating immune cells to the cochleae in mice post noise exposure were significantly reduced with oseltamivir treatment, suggesting an anti-inflammatory mechanism of action. Cisplatin-induced hearing loss was measured in a multi-dose cisplatin clinical regimen and hearing protection was observed with a dose of 10 mg/kg oseltamivir given twice a day, which is 66% of the mouse equivalent of the standard adult influenza dose. 

Overall, the new studies support tizaterkib as a promising otoprotective therapeutic candidate for traumatic noise exposure, and dabrafenib and oseltamivir as promising ototprotective candidates for cisplatin treatment.