The long-term goal of this work is to develop a curative treatment for congenital deafness, vestibular dysfunction and retinitis pigmentosa in Usher syndrome, the leading genetic cause of combined deafness and blindness. This treatment approach could ultimately be developed as a therapeutic for hearing, balance and vision loss in general. In this project, we investigate the use of antisense oligonucleotides (ASOs) for the treatment of Usher syndrome in mice. We designed an ASO to correct an RNA splicing defect caused by a mutation in the USH1C gene that causes Usher syndrome in mice and humans. Preliminary results show that an USH1C-targeted ASO rescues hearing and vestibular function in mice.
The aims of this project are to further develop this ASO-targeting approach by 1) Developing an ASO-based treatment regimen for the prevention/ treatment of deafness and blindness in mice;2) Assessing the cellular effects of USH1C-targeted ASOs and establishing measurable outcomes of treatment efficacy;and 3) Delivering ASOs locally to the mouse cochlea to improve targeting efficacy. The overall goal of these aims is to translate this ASO-targeting approach into a treatment regimen that will lay a foundation for future clinical trials. One far-reaching contribution of this study is the demonstration that ASOs can effectively and potently target the cochlea to rescue hearing, a finding that advocates ASOs as a promising tool for treating diseases of the ear.

Public Health Relevance

Hearing impairment is the most common sensory deficit in humans. Usher syndrome is the leading genetic cause of combined deafness and blindness and is the focus of this project that aims to develop a cure for hearing impairment, vestibular dysfunction and retinitis pigmentosa associated with the disease. Success in this project will advance a treatment paradigm for deafness based on antisense oligonucleotide (ASO) technology that could be applied to a broad-range of hearing, vision and balance disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC012596-01A1
Application #
8496335
Study Section
Special Emphasis Panel (ZDC1-SRB-L (46))
Program Officer
Watson, Bracie
Project Start
2013-02-05
Project End
2017-01-31
Budget Start
2013-02-05
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$330,969
Indirect Cost
$81,069
Name
Rosalind Franklin University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064
Havens, Mallory A; Duelli, Dominik M; Hastings, Michelle L (2013) Targeting RNA splicing for disease therapy. Wiley Interdiscip Rev RNA 4:247-66
Lentz, Jennifer J; Jodelka, Francine M; Hinrich, Anthony J et al. (2013) Rescue of hearing and vestibular function by antisense oligonucleotides in a mouse model of human deafness. Nat Med 19:345-50