A novel pyridoindole improves the recovery of residual hearing following cochlear implantation after a single preoperative application

Sensorineural hearing loss (SNHL) is the most common sensory deficit worldwide. Due to the heterogeneity of causes for SNHL, effective treatment options remain scarce, creating an unmet need for novel drugs in the field of otology. Cochlear implantation (CI) currently is the only established method to restore hearing function in profound SNHL and deaf patients. The cochlear implant bypasses the non-functioning sensory hair cells (HCs) and electrically stimulates the neurons of the cochlear nerve. CI also benefits patients with residual hearing by combined electrical and auditory stimulation. However, the insertion of an electrode array into the cochlea induces an inflammatory response, characterized by the expression of pro-inflammatory cytokines, upregulation of reactive oxygen species, and apoptosis and necrosis of HCs, putting residual hearing at risk. Here, we characterize the effects of the small molecule AC102, a pyridoindole, for its protective effects on residual hearing in CI. We show that AC102 significantly preserves hearing thresholds across the whole cochlea and confines the cochlear trauma to the directly mechanically injured area. In addition, AC102 significantly preserves auditory nerve fibers and inner HC synapses throughout the whole cochlea. AC102s effects are likely elicited during the inflammatory phase of electrode insertion trauma (EIT) and mediated by anti-apoptotic and anti-inflammatory properties, as uncovered by an in vitro assay of ethanol induced apoptosis and evaluation of mRNA expression of pro-inflammatory cytokines in an organotypic ex vivo model of EIT. The results in this study highlight AC102 as a promising compound for the attenuation of EIT during CI. Moreover, as the inflammatory response in cochlear implantation shares similarities to other etiologies of SNHL, a beneficial effect of AC102 can be inferred for other inner ear conditions as well. ### Competing Interest Statement Christoph Arnoldner is currently holding a grant from the Christian Doppler Research Association (CD Laboratory for Inner Ear Research) and is receiving funding from MED-EL Corporation, Innsbruck, Austria. Michael Nieratschker, Erdem Yildiz, Anselm J. Gadenstaetter and Matthias Gerlitz were financed by this funding while conducting the studies. Susanne Braun and Pavel Mistrik are employed by MED-EL as Senior Research Specialists and were involved in conceptualization of the study design. Reimar Schlingensiepen and Hans Rommelspacher are CEO and CSO of AudioCure Pharma GmbH. Both had no involvement during conduction of the study or during analysis of the results. Monika Kwiatkowska and Sujoy Bera are employees of Audiocure Pharma GmbH. Lukas D. Landegger receives research funding from Decibel Therapeutics and Amgen and has worked as an independent consultant for Gerson Lehrman Group and Conclave Capital.