Spiral Ganglion Health: from Genomics to Gene Therapy

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PROJECT ABSTRACT Congenital hearing loss affects 1 in 500 newborns, making it the most common sensory disorder in humans. Children with hearing loss are at risk for poor speech, language, and social development with noted negative effects on quality of life. The most effective treatment for severe-to-profound hearing loss in children is cochlear implantation. The cochlear implant (CI) is the most successful and widely used sensory prosthesis in humans and cochlear implantation has restored hearing to hundreds of thousands around the world. While the majority of CI users experience significant improvement in speech perception, a significant portion do not. There is a critical need to identify individuals at-risk for poor outcomes prior to cochlear implantation in order to: (1) provide accurate pre-operative counseling, (2) tailor post-operative care, and (3) develop new treatment strategies for these types of hearing loss. To date, the best predictors of CI speech perception outcomes rely on complex statistical modeling of clinical factors associated with hearing loss or intra-operative electrocochleography (ECoG), neither of which can be routinely used pre-operatively. There is increasing evidence that specific genetic variations that negatively affect the health of spiral ganglion neurons (SGNs) are associated with worse postoperative CI speech perception outcomes. The primary goal of this grant proposal is to better understand genetic contributors to postoperative speech perception outcomes in children. We recently showed that variations in the gene TMPRSS3 are associated with worse CI speech perception outcomes. Although TMPRSS3 is one of the most common causes of genetic hearing loss, the function of the TMPRSS3 protein and the mechanism by which it causes hearing loss are not known. TMPRSS3 is involved in expression of calcium- sensitive potassium channels in inner hair cells. A knock-out mouse model shows rapid hair cell degeneration soon after the onset of hearing. However, deafness-causing mutations in TMPRSS3 are notable for causing not only a severe-to-profound congenital hearing loss (DFNB10) but also a later onset post-lingual hearing loss (DFNB8). In addition, the expression of TMPRSS3 includes hair cells and also SGNs. We hypothesize that TMPRSS3 has functions in the inner hair cells as well as in the SGN. The aims of this project are to: (1) examine the complex interplay between genetics, ECoG, and post-operative speech perception scores in children with CIs, (2) improve our understanding of TMPRSS3 through development of a new mouse model for late onset DFNB8 hearing loss, and (3) develop a new gene therapy for TMPRSS3 hearing loss. The expected results of this study will be: (1) a genetic risk index for poor CI outcomes in children, (2) a better understanding of the function of TMPRSS3 in hearing and hearing loss, and (3) a novel gene therapy for TMPRSS3 hearing loss. The results of this study will have direct clinical impact as well as pave the way for future gene therapy trials in humans.