# Development of Genome Editing as Treatment for Genetic Hearing Loss

> **NIH NIH R01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2021 · $425,000

## Abstract

Project Summary and Relevance
Dementia including Alzheimer’s disease (AD) is manifested in aging population, yet all the clinical trials
over the years failed to halt or revise the progression of the diseases. The prevalence of the diseases
increases with age and will present as ever larger burden in future given the disproportional increase in
aging population worldwide. Studies have suggested an association between sensory disorders such as
hearing, visual, and olfactory impairments with cognitive decline in older adults although these
associations are complex and can exhibit bidirectionality. Several hypothetical mechanisms have been
proposed, such as a common pathophysiology or a cause-effect relationship between sensory deficits and
dementia and Alzheimer’s disease. However, it remains to be determined if and the extent to which
hearing loss contributes to dementia or Alzheimer’s disease and if rescue of hearing could lessen disease
phenotypes. Recently hearing loss has been hypothesized to play a role as one of the largest modifiable
risk factors for dementia and Alzheimer’s disease. The availability of mouse models for hearing loss and
AD makes it possible to directly evaluate if hearing loss, manifested in young or adult age, contributes to
AD on the functional and structural measures. In this administration supplement, we will leverage our
work in editing therapy to treat genetic deafness mouse models due to dominant mutations in the
Pmca2(Atp2b2)gene and microRNA mir96 to establish if early onset hearing loss in the Pmca2 mice and
progressive hearing loss in the mir96 mice contribute to AD disease phenotype in two well-characterized
AD mouse models (5xFAD and 3xTg-AD, due to expression of human APP and PSEN1 transgenes). This
will be done by introducing Pmca2 and Mir96 mutations into the AD background and by studying if the
AD phenotypes in behavior (spatial working memory, impaired learning, cortex-dependent remote
memory, fear conditioning and motor impairment) is exacerbated by hearing loss. Cellular events
including astrogliosis and microgliosis, synaptic degeneration and neuron loss will also be compared. Our
ongoing R01 work has demonstrated that editing therapy robustly rescues hearing in the Pmca2 mice and
we have optimized sgRNA to editing the mir96 mutation to rescue hearing. By selecting hearing loss
models that can be treated successfully by editing therapy, we will determine if hearing rescue leads to
lessening of the progression of the AD phenotypes. The study will provide the insight into the mechanism
of interactions between hearing loss and Alzheimer’s disease, and to establish the potential of
personalized hearing loss therapy on the progression of Alzheimer’s disease.

## Key facts

- **NIH application ID:** 10288164
- **Project number:** 3R01DC016875-03S1
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Zheng-Yi Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $425,000
- **Award type:** 3
- **Project period:** 2019-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10288164

## Citation

> US National Institutes of Health, RePORTER application 10288164, Development of Genome Editing as Treatment for Genetic Hearing Loss (3R01DC016875-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10288164. Licensed CC0.

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