Title: Understanding and treating high frequency age-related hearing loss
Funder: Dunhill Medical Trust

Abstract: Hair cells in the high-frequency cochlear region are the primary target in agerelated hearing loss (ARHL) in both mice and humans. However, we still do not fully understand the mechanisms underlying this vulnerability. Studies in C57BL/6N mice have shown that a single nucleotide polymorphism in Cadherin-23 (Cdh23-753A) causes early-onset ARHL. The loss of hearing at high frequencies can be rescued by gene editing Cdh23-753A to Cdh23-753G. It is therefore important to study how a single gene is able to change our hearing ability across different frequencies and how this could be prevented. The first aim of this project is to understand how Cdh23-753A differentially affects hearing at high- and low-frequencies. I will test the hypothesis that Cdh23-753A has a more profound effect on mechanoelectrical transduction in high-frequency hair cells using C57BL/6N and the co-isogenic C57BL/6N-Cdh23+ (Cdh23-repaired) mouse strains. The mechanoelectrical transducer current and stereociliary bundle structure in hair cells will be studied using electrophysiology and electron microscopy. The second aim of the project is to test the hypothesis that ARHL caused by Cdh23-753A can be prevented using gene-based therapy in vivo, which is currently one of the most promising therapeutic intervention in humans to cure genetic diseases. This will be done by using AAV vectors to express “normal” Cdh23 in C57BL/6N mice. Overall, this project will provide a physiological understanding of the mechanisms underpinning Cdh23-dependent ARHL, and provide the proof-of-principle for the future development of gene-based therapy for it.

Lay abstract: a. Background and need for the research About one in three of us is expected to experience progressive hearing loss by the age of 50 years old. Age-related hearing loss (ARHL) is a complex disorder, where the symptoms can vary between patients. ARHL can start as early as 20’s or as late as 60’s and ranging from a detectible hearing loss up to difficulties in understanding speech, especially in noise. Nevertheless, in most cases, ARHL affects our ability to detect high frequencies, which we experience as a telephone ring or a music piece. Although ARHL largely affects the quality of life, we still do not fully understand why some people start to lose hearing with age, which hinders our ability to develop effective treatments for it. One hypothesis is that ARHL is at least in part caused by the dysfunction of sound transducing cells in the cochlea called hair cells. These cells are the key to transducing sounds into electrical signals that can be processed by the brain. b. Aim of the project The aim of this project is to understand why the hair cells in the high-frequency cochlear region are more vulnerable to cochlear ageing, and the to identify potential therapeutic target for a gene-base therapy. c. An outline of the research methods Recent studies have identified a mutation in a gene called cadherin 23 (Cdh23), which leads to an accelerated form of ARHL in mice. Therefore, my proposal is aimed at investigating why and how Cdh23 is key to develop ARHL. This will be done by comparing the function and structure of the hair cells from mutant mice with those in which the Cdh23 gene has been repaired. I will be using state-or-the-art experimental approaches, such as electrophysiology and electron microscopy, which allow to measure electrical signals at a microsecond scale and cellular structures at nanometrescale. These approaches, will be used to compare hair cells responding to low- and high-frequency sounds from the above mouse models. I will also use gene therapy to test whether ARHL can be treated by expressing normal Cdh 23 in mice carrying the mutation. d. How people with hearing loss or tinnitus will benefit from the research This proposal is designed to test whether gene-based therapy, an approach that is currently used in hospital to treat other disorders, is able to delay the normal progression of ARHL in mice. This will provide the initial proof-of-principle for the future development of treatments in humans for ARHL. This research will also provide the basis for treatment for other Cdh23-induced deafness, such as a type of Usher Syndrome.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.2 CELLULAR AND GENE THERAPIES
Health categories: EAR