Suzanne de Bruijn

161 The development of a genetic therapy for DFNA21 AON chemistry are not completely comparable, these data suggest a repetition rate of gapmer treatments for inner ear disorders of once or twice a year. In comparison, weekly or daily intratympanic injections, albeit for a short period of time, are an established treatment regimen for several other inner ear therapeutics. 32-34 Despite the technical feasibility of repeated intratympanic injections, there are significant knowledge gaps in terms of AON uptake, biodistribution and half-life in the cochlea and auditory hair cells that need to be addressed before further clinical development of gapmer AON treatments for DNFA21 and other forms of dominantly inherited HL can be initiated. In conclusion, based on the results obtained in this study and the developments in inner ear therapeutics, we consider AON 6 as a potent molecule to treat DFNA21 in the future. Although there are still some avenues to be explored to further optimize the molecular efficacy of the AON, the results obtained in the current study warrant further preclinical development of the lead molecule in advanced cellular models and animal models. With successful application of AON therapies for many other inherited disorders, and the rapid developments in the fields of AON therapeutics and cochlear drug delivery, we are confident that the specific challenges for inner ear AON therapeutics will be resolved in the future. ACKNOWLEDGEMENTS The authors thank Hedwig Velde for her help with tissue collection and Saskia van der Velde-Visser, Marlie Jacobs-Camps and Anita Roelofs for their contributions to cell culture. This study was funded by a DCMN Radboudumc grant (to H.K. and F.P.M.C.).