Gene Therapy for Genetic Hearing Loss
What is 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.
How is gene therapy used to treat hearing loss?
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.
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Narrator: Our team at Children's Hospital of Philadelphia wants to help you understand in vivo gene therapy. But before we can get into what in vivo means, we should start by explaining what is gene therapy? Gene therapy is a way to treat or prevent disease by using genetic material like DNA. First, the basics.
Our bodies are made up of cells. And inside each cell is its DNA. DNA is divided into short sections called genes. Genes act as instruction manuals, telling our cells how to make proteins. Proteins are necessary for our bodies to function. Proteins do important work like helping us digest food and helping our blood clot when we get a cut.
But sometimes, a gene's instructions for making a protein are not correct. This can cause changes in how a protein works. These incorrect instructions can result in a genetic disease. Gene therapy can deliver new instructions to the body to make proteins that function correctly.
Hannah: I was going blind. After I received a healthy gene to replace the bad gene in my eyes, I was able to see so much better.
Narrator: How does gene therapy work? There are two types of gene therapy. Ex vivo and in vivo. Ex vivo means outside the body. When a child receives ex vivo gene therapy, it means their cells are removed from their body, treated with gene therapy, and then put back into their body. In vivo means inside the body.
Let's talk more about how in vivo gene therapy works. When a child receives in vivo gene therapy, we use something called a vector, which acts like a delivery truck. Vectors with the new or corrected gene can get into the body through an iv, or doctors can put them in a specific spot, like the eye. The vector then travels to the cells where the corrected gene is needed.
With the help of the new gene, the cells start making the proper kind of protein. One condition that can be treated with an in vivo gene therapy, is spinal muscular atrophy, which is a nerve disease that used to be fatal for children with a severe type. Children with a disease now can receive an in vivo gene therapy that stops the progression of the condition.
William: Because of spinal muscular atrophy, I couldn't even roll over after gene therapy. I can now stand and take steps.
Narrator: Gene therapy is changing and saving children's lives and CHOP has been at the forefront of gene therapy breakthroughs from the start. CHOP was the first in the world to use in vivo gene therapy delivered into the bloodstream, which is the most commonly used method today.
And we've pioneered many other groundbreaking discoveries. Our determined researchers are exploring the use of in vivo gene therapy for all kinds of diseases so that more children worldwide will have bright futures.
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.
Treatment options for genetic hearing loss at CHOP
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.