# Spiral Ganglion Health: from Genomics to Gene Therapy

> **NIH NIH K08** · BOSTON CHILDREN'S HOSPITAL · 2021 · $193,037

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10284638
- **Project number:** 1K08DC019716-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Aiden Eliot Shearer
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $193,037
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10284638

## Citation

> US National Institutes of Health, RePORTER application 10284638, Spiral Ganglion Health: from Genomics to Gene Therapy (1K08DC019716-01). Retrieved via AI Analytics 2026-06-04 from https://api.ai-analytics.org/grant/nih/10284638. Licensed CC0.

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