AWARD NUMBER: W81XWH-15-1-0472 TITLE: Preclinical Validation of Novel Fluorescently Labeled Compounds to Treat Neurodegenerative Hearing Loss PRINCIPAL INVESTIGATOR:

Introduction: As otology enters the field of gene therapy and human studies commence, the questionarises whether audiograms e the current gold standard for the evaluation of hearing function e canconsistently predict cellular damage within the human inner ear and thus should be used to defineinclusion criteria for trials. Current assumptions rely on the analysis of small groups of human temporalbones post mortem or from psychophysical identification of cochlear “dead regions” in vivo, but acomprehensive study assessing the correlation between audiometric thresholds and cellular damagewithin the cochlea is lacking.Methods: A total of 131 human temporal bones from 85 adult individuals (ages 19e92 years, median 69years) with sensorineural hearing loss due to various etiologies were analyzed. Cytocochleograms ewhich quantify loss of hair cells, neurons, and strial atrophy along the length of the cochlea e werecompared with subjects' latest available audiometric tests prior to death (time range 5 he22 years,median 24 months). The Greenwood function and the equivalent rectangular bandwidth were used toinfer, from cytocochleograms, cochlear locations corresponding to frequencies tested in clinical audio-grams. Correlation between audiometric thresholds at clinically tested frequencies and cell type-specificdamage in those frequency regions was examined by calculating Spearman's correlation coefficients.Results: Similar audiometric profiles reflected widely different cellular damage in the cochlea. In ourdiverse group of patients, audiometric thresholds tended to be more influenced by hair cell loss than byneuronal loss or strial atrophy. Spearman's correlation coefficient across frequencies was at most 0.7 andoften below 0.5, with 1.0 indicating perfect correlation.Conclusions: Audiometric thresholds do not predict specific cellular damage in the human inner ear. Ourstudy highlights the need for better nonor minimally-invasive tools, such as cochlear endoscopy, toestablish cellular-level diagnosis and thereby guide therapy and monitor response to treatment.© 2016 Elsevier B.V. All rights reserved.