Michael Hildebrand - Non-Syndromic Deafness; gene therapy

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Hearing loss is the most common human sensory defect. Genetic forms of sensorineural hearing loss have a profound impact on a patient’s quality of life. In 70% of hereditary cases hearing impairment is the only symptom (non-syndromic hearing loss; NSHL). We are investigating the genetic causes of both dominant and recessive forms of NSHL. Gene identification in small families segregating autosomal dominant NSHL presents a significant challenge. To address this challenge, we have developed a machine learning based software tool, AudioGene v2.0, to prioritize candidate genes for mutation screening based on audioprofiling. We analyzed audiometric data from a cohort of American families with high frequency autosomal dominant NSHL. Those families predicted to have a DFNA2 audioprofile by AudioGene v2.0 were screened for mutations in the KCNQ4 gene. Two novel missense mutations and a stop mutation were detected in three American families predicted to have DFNA2-related deafness for a positive predictive value of 6.3%. The false negative rate was 0%. The missense mutations were located in the channel pore region and the stop mutation was in transmembrane domain S5. The latter is the first DFNA2-causing stop mutation reported in KCNQ4. Our data suggest: (1) that the N-terminal end of the P-loop is crucial in maintaining the integrity of the KCNQ4 channel pore; and, (2) that AudioGene audioprofile analysis can effectively prioritize genes for mutation screening in small families segregating high frequency autosomal dominant NSHL. AudioGene software will be made freely available to clinicians and researchers once it has been fullly validated.   

 Development of effective therapeutics for hearing loss has proven to be a slow and difficult process, evidenced by the lack of restorative medicines and technologies currently available to the otolaryngologist. In large part this is attributable to the absence of regenerative potential in cochlear cells and the secondary degeneration of the cochlear architecture that commonly follows sensorineural hearing impairment. Therapeutic advances have been made using animals models, particularly in regeneration and remodeling of spiral ganglion neurons which retract and die following hair cell loss. Replacement of hair cells appears to be a more complex task, although natural regeneration in avian and reptilian systems provides hope that it is achievable in humans. The most exciting recent advancements in this field have been made in the relatively new areas of cellular replacement and gene therapy. We are currently developing a gene-based therapy for hearing loss at the human DFNA2 locus, a common site of dominantly inherited hearing loss in humans. We are testing whether siRNA-mediated post-transcriptional silencing of dominant negative alleles of KCNQ4 and/or supplementation of wild-type KCNQ4 will preserve auditory function in a mouse model of human DFNA2 hearing loss. This may lead to a treatment option for families with DFNA2 hearing loss. This approach will also be applicable to other forms of hereditary hearing loss.