# Fetal gene therapy for congenital deafness and imbalance

> **NIH NIH R21** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $26,611

## Abstract

PROJECT SUMMARY/ABSTRACT
Extensive knowledge of the genetic mutations responsible for congenital hearing loss and imbalance has led to
gene-based therapeutic strategies aimed at rescuing sensory function. The mouse is the dominant model system
because of the availability of natural and induced mutations, the accessibility of the neonatal inner ear, and its
responsiveness to genetic manipulation. A striking observation from these studies is that virus-mediated gene
therapies and pharmacotherapies targeted to the postnatal day 0 (P0) through P5 mouse inner ear yield optimal
rescue of hearing and balance. Intervention thereafter dramatically lessens or entirely eliminates therapeutic
benefits. Critically, the P0-P5 mouse inner ear is functionally immature with hearing onset at P12 consonant with
the emergence of the acoustic startle reflex. In humans, acoustic startle arises at gestational week 19 during the
second trimester of pregnancy, suggesting that the window of therapeutic efficacy from P0-P5 in the mouse may
predicate a prenatal window of efficacy in the human fetus. The conceptual basis of this proposal is that the early
neonatal mouse inner ear functionally models the prenatal human inner ear. To discern if gene therapies defined
in the early neonatal mouse inner ear may safely and effectively translate to the clinic, a higher vertebrate model
system characterized by the precocious emergence of fetal hearing is needed. Our long-term goal is to establish
a rhesus macaque model system to test fetal versus neonatal gene therapy to treat congenital deafness and
imbalance. In Aim 1, we will define the onset of fetal hearing in the rhesus macaque. Pure tones at 100, 250,
500, 1000, or 3,000 Hz will be transmitted across the maternal abdomen with increasing intensities. Ultrasonic
assessment of acute head, arm, or torso movements will indicate startle. We predict that startle to lower
frequency stimuli will emerge first during development as they do in the human fetus. We further hypothesize
that the optimal time to intervene therapeutically will precede the age of hearing onset. In Aim 2, we will define
a fetal survival surgery to access the inner ear. An adeno-associated viral vector encoding green fluorescent
protein (GFP) will be microinjected into membranous labyrinth. The viral transduction efficiency will be estimated
by whole mount immunofluorescence to detect GFP. We hypothesize that an AAV2-based vector pseudotyped
with a synthetic or naturally occurring capsid will robustly transduce the majority of immature hair cells in the
fetal inner ear. In Aim 3, a CRISPR/Cas9-based genome editing technology will be deployed to create rhesus
embryos with bi-allelic mutations in harmonin. We hypothesize that correct targeting will produce a model of
Usher syndrome type 1C characterized by congenital deafness and profound vestibular dysfunction. Successful
completion of the proposed studies will define the optimal gestational age to initiate fetal ...

## Key facts

- **NIH application ID:** 10475412
- **Project number:** 3R21DC018126-02S1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** JOHN Vincent BRIGANDE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $26,611
- **Award type:** 3
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475412

## Citation

> US National Institutes of Health, RePORTER application 10475412, Fetal gene therapy for congenital deafness and imbalance (3R21DC018126-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475412. Licensed CC0.

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