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Publikationssystem UB Tuebingen advisor Burgalossi, Andrea (Prof. Dr.) author Becker, Franziska 2025-12-03T14:53:21Z 2026-12-31 http://hdl.handle.net/10900/172805 Die Dissertation ist gesperrt bis zum 31. Dezember 2026 ! Hearing is a complex sensory process in which sound waves are captured by the outer ear, amplified by the middle ear, and converted into electrical signals in the inner ear. This transduction occurs in the cochlea through specialized hair cells within the organ of Corti, which transform mechanical vibrations into neural impulses. These signals are then transmitted via the auditory nerve to central auditory structures. Accurate synaptic transmission from inner hair cells to spiral ganglion neurons is essential for the correct perception of sound intensity, frequency, and spatial localization, but especially for speech recognition. The hereditary hearing disorder DFNB9 is an autosomal recessive form of congenital, non-syndromic, sensorineural deafness caused by mutations in the OTOF gene. This gene encodes otoferlin, a key protein involved in synaptic exocytosis in inner hair cells. Depending on the nature and severity of the mutation, DFNB9 usually leads to either mild to moderate hearing loss with preserved speech understanding or to profound congenital deafness with complete loss of speech understanding. Current clinical therapy primarily relies on cochlear implants, which bypass the defective synaptic transmission by directly stimulating the auditory nerve electrically. Recently, early clinical studies in children affected by DFNB9 have shown that gene therapy approaches can restore hearing thresholds to normal levels. Despite these promising results, significant knowledge gaps remain regarding the pathophysiology of OTOF-associated hearing loss, particularly concerning outer hair cell function. Therefore, detailed phenotypic characterization of various Otof mouse models is essential for optimizing the safety and efficacy of future gene therapies in humans. This doctoral thesis aims to comprehensively study a mouse model carrying the most prevalent OTOF mutation found in humans, p.Gln829Ter. The primary objective of this basic research is to thoroughly characterize the phenotype of this variant in order to define the optimal therapeutic time window and minimize potential side effects. Another focus of this work is the evaluation of alternative methods for the analysis of gene therapy-treated inner ears. While conventional whole mount preparations of the organ of Corti are commonly used for immunohistochemical analysis, they are technically demanding and often result in tissue loss. In this study, the tissue clearing method was systematically evaluated and adapted to the murine cochlea. Tissue clearing is a technique in which refractive index mismatches are equalized to minimize light scattering in intact tissue, thereby enabling deeper optical penetration. This approach enables three-dimensional visualization and quantification of otoferlin expression, in particular the integrity of the hair cells, after gene therapy without structurally compromising the tissue. The final part of this thesis investigates whether individuals affected by DFNB9 exhibit increased sensitivity to noise exposure. Since otoacoustic emissions are typically lost within the first two decades of life in DFNB9 patients, it is hypothesized that outer hair cells may be more vulnerable to acoustic stress due to the lack of synaptic activity. It is therefore crucial to investigate whether, due to the lack of efferent inhibition during noise exposure, outer hair cells lose function or if the cells themselves undergo degeneration. This question will be addressed through controlled noise trauma experiments in Otof mouse models, aiming to contribute to the development of more differentiated treatment strategies for individuals with DFNB9. en ubt-podno Exploring Inner Ear Models and Imaging Techniques: A Basis for Future Gene Therapy of Otoferlin-Related Deafness PhDThesis URL https://publikationen.uni-tuebingen.de/xmlui/bitstream/10900/172805/2/Franziska%20Becker_Dissertation%20Otoferlin-Related%20Gene%20Therapy.pdf File MD5 45a96212cf6c6f6e4c15dbc35c62144e 5706523 application/pdf Franziska Becker_Dissertation Otoferlin-Related Gene Therapy.pdf URL https://publikationen.uni-tuebingen.de/xmlui/bitstream/10900/172805/3/Franziska%20Becker_Dissertation%20Otoferlin-Related%20Gene%20Therapy.pdf.txt File MD5 b82da1d6a95fbc0f1ccccc1944076db9 237928 text/plain Franziska Becker_Dissertation Otoferlin-Related Gene Therapy.pdf.txt