Whirlin gene therapy restores stereocilia bundles (red) in the inner ear of a whirler mutant mouse to normal length and position. Even after four months, stereocilia continue to produce whirlin protein (green), helping to maintain the structure and function of the stereocilia and improving the mouse’s ability to hear and maintain balance.
Using gene therapy, scientists have corrected defective structures in the inner ears of newborn mice, with long-term benefits. The study is one of the first to use gene therapy successfully to improve hearing and restore balance in mice with a type of inherited deafness, also found in people, called Usher syndrome. Conducted by researchers at the National Institute on Deafness and Other Communication Disorders (NIDCD), part of the National Institutes of Health, the results were published in the March 2017 issue of Molecular Therapy. The findings support growing evidence that gene therapy could be an effective treatment for inherited types of hearing loss, deafness, and balance disorders.
Usher syndrome is a genetic disorder that affects both hearing and vision. It is the most common cause of inherited blindness and deafness. Approximately 3 to 6 percent of all children who are deaf and another 3 to 6 percent of children who are hard-of-hearing have Usher syndrome. In developed countries, such as the United States, about four newborns in every 100,000 births have Usher syndrome. People with Usher syndrome can also have balance problems because the disease affects the inner ear, which houses key structures for balance as well as hearing.
There is currently no way to prevent hearing loss or balance problems associated with Usher syndrome, which worsen over time; however, hearing aids and cochlear implants may be used to improve hearing in these patients.
The experimental gene therapy used in the study targets sensory cells in the inner ear called hair cells. These hair cells have hair-like projections called stereocilia, which help detect and process incoming sound and information about movement to guide a person’s sense of balance. Stereocilia need whirlin protein to fully grow and function properly. In one type of Usher syndrome, the gene that encodes whirlin protein is mutated. This causes the stereocilia to be abnormally short and disorganized, making them dysfunctional. As a result, the sensory hair cells in the inner ear cannot detect sound and information about movement to guide the sense of balance, leading to hearing loss or deafness, and dizziness.
Scientists supported by the NIDCD have been exploring ways to restore hearing and balance caused by Usher syndrome using gene therapy in a mouse model called the whirler mouse. Like people with Usher syndrome, the whirler mouse has a mutation in the whirlin gene that makes the hair cells in the inner ear dysfunctional.
NIDCD Surgeon-Scientist Wade Chien, M.D., who leads the NIDCD Inner Ear Gene Therapy Program, and his team at the NIDCD used an adeno-associated virus to deliver normal copies of the whirlin gene into the inner ears of whirler mice. The whirlin gene therapy restored the size and positions of the stereocilia in the inner ear. In addition, hearing was improved and balance was restored in the treated mice; in some mice, the benefits lasted up to four months.
Chien, a neurotologist who is also affiliated with Johns Hopkins University, reported in 2015 that he and colleagues had successfully restored stereocilia in whirler mice in a similar study; however, the whirlin gene therapy improved only a small percentage of the stereocilia, and the treatment did not improve hearing.
In the new study, Chien and his team of scientists provided the same whirlin gene therapy to similar mice, but changed the location of the injection within the inner ear. This time, they injected the whirlin gene through the posterior semicircular canal instead of the cochlea. The therapy reached more hair cells and stereocilia throughout the inner ear than in the previous study, leading to improved hearing and balance.
This work was supported within the intramural laboratories of the NIDCD (projects DC000082, DC000079, DC000048, DC000080, and DC000060). Additional support was provided by the NIDCD Mouse Auditory Testing Core Facility and the Nebraska Tobacco Settlement Biomedical Research Development Fund.
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