Gene Therapy for Genetic Hearing Loss

Some forms of hearing loss are caused by genetic mutations. (Hearing loss can also be caused by illness, injury, aging, exposure to loud noises or a problem in how the inner ear is formed.) Approximately 150 genes have been linked to sensorineural hearing loss. Sensorineural hearing loss means that there is a malfunction or damage in the inner ear that causes loss of hearing.

Since hearing is a complicated function involving many different parts of the inner ear, researchers are working to identify which genetic mutations affect which part of the ear. They’re also working to find out specifically which cells are affected. 

Researchers have determined that one of the genetic causes of sensorineural hearing loss is when the otoferlin (OTOF) gene doesn’t work properly. The OTOF gene is located in sensory cells in the cochlea. The cochlea is a spiral-shaped part of the inner ear that contains some 30,000 of these sensory cells. The sensory cells transform sound waves into electrical impulses that are sent to the brain via the auditory nerve so we can hear.

The first gene therapy being tested for hearing loss seeks to replace the nonfunctioning OTOF gene in the cochlea with a working copy of the OTOF gene. This gene was selected because of its important role in the hearing process.

Gene therapy for children with OTOF gene-related deafness seeks to restore hearing by injecting copies of normal OTOF genes into the inner ear. With normal OTOF genes, the sensory cells will be able to function so they can respond to sound and activate the auditory nerve to send impulses to the brain. Functioning OTOF genes are encased in a viral vector, a modified form of a non-disease-causing virus, so they can be delivered into cochlear cells in the inner ear. This is an in vivo gene therapy.

Because the cochlea is encased on a bony chamber that is difficult to reach, the gene therapy is delivered to the inner ear using a special device, in a minimally invasive surgical procedure developed at Children’s Hospital of Philadelphia. The gene therapy is placed into the inner ear using a device called an endoscope that lifts up the ear drum, allowing a special probe to reach the “round window,” a tiny area that leads to the cochlea. A single, very small dose of normal OTOF genes is then delivered to the inner ear.

After the procedure, which requires an overnight stay in the hospital, children are monitored for two years for any side effects. The aim is for the normal OTOF genes to function in the cochlea and replace the faulty genes, restoring a child’s hearing. Patients will undergo a series of follow-up audiology tests to determine if their hearing improves.

Depending on the type and severity of genetic hearing loss, children may be treated by the Cochlear Implant Program.

At CHOP’s Cochlear Implant Program, we evaluate children with severe to profound hearing loss and treat eligible children with the implant and provide ongoing follow-up care.

The Department of Audiology sees children with a range of hearing loss issues and will work with parents to find the most appropriate treatment option for each child. Children with milder forms of genetic hearing loss may be treated with hearing aids.

At this time, there is not a Food and Drug Administration-approved gene therapy for hearing loss.

Clinical trials for genetic hearing loss

There is currently an active gene therapy clinical trial for otoferlin (OTOF) gene-related hearing loss. CHOP is one of several clinical trial sites in the world participating in the AK-OTOF-101 clinical trial, sponsored by Akouos Inc., a wholly owned subsidiary of Eli Lilly and Co.

CHOP treated the first patient in the United States with this gene therapy in October 2023. Read more about this breakthrough treatment.

To be eligible, children must be age 2 to 17 years old and have profound deafness in both ears caused by a defective OTOF gene. Children are not eligible if they have already received cochlear implants in both ears.

 Learn more about the study requirements here.