The first gene therapy to treat inherited deafness was approved by the Food and Drug Administration in April, a breakthrough that was made possible with the help of decades-long research led by Lawrence R. Lustig, M.D., otolaryngologist-in-chief at NewYork-Presbyterian and Columbia and chair of the Department of Otolaryngology-Head and Neck Surgery at Columbia.
The dual adeno-associated virus (AAV) vector-based gene therapy, known under the commercial name Otarmeni (lunsotogene parvec-cwha), treats a rare form of inherited deafness caused by a mutation in the OTOF gene, which produces otoferlin, a protein critical for synaptic transmission. Otoferlin deafness accounts for 1% to 3% of congenital deafness cases, with just 20 to 50 babies per year born with the condition.
Dr. Lustig spent years developing animal models to target inherited deafness and helped design the human trial to test the otoferlin gene therapy, known as the CHORD study. The results, which showed that 75% of patients who received the one-time gene therapy experienced significant hearing improvements, were published in the New England Journal of Medicine and helped expedite FDA approval. The therapy will be available for free to U.S. patients.
“This approval is poised to fast-forward the entire field of gene therapy for genetic deafness,” says Dr. Lustig.
In a majority of patients, we’ll start to see improvement of the hearing thresholds over the first six to 12 weeks.
— Dr. Lawrence Lustig
How Otoferlin Gene Therapy Works
The otoferlin protein works as a calcium sensor in the inner hair cells of the ear and regulates synaptic transmission traveling from the sensory inner hair cells to the cochlear nerve. When children are born with otoferlin deficiency, it typically results in profound deafness. Cochlear implants have been effective for many of these patients, but they do not restore natural hearing, and there are some limits to understanding speech and enjoying music.
In the CHORD study, the investigators used a dual AAV vector to deliver a working OTOF gene to the hair cells. Using dual vectors allowed them to deliver a greater amount of genetic material in a single infusion, an approach that Dr. Lustig had first experimented with in mouse models in his research lab at the University of California, San Francisco.
The challenge with OTOF is its size — it is too big for a single AAV vector. Researchers split the gene in half, engineered “sticky” ends on both halves, and put each into a separate AAV vector. “When you co-transfect these and both halves get into the cell, the sticky ends recombine, cut themselves out, and you’re left with the full-length segment of RNA that allows the protein to be made normally,” Dr. Lustig says.
Administering the gene therapy is similar to cochlear implantation surgery. Patients are put under general anesthesia, and a small incision is made behind the ear. Surgeons drill through the mastoid bone to access the middle ear, and then a small opening is made into the inner ear to allow for infusion of the gene therapy via catheter. At the same time, a second microscopic opening is made into one of the balance canals, which allows for flushing of the cochlear fluids to enable better gene delivery throughout the inner ear. The infusion takes about 15 minutes.
“In a majority of patients, we’ll start to see improvement of the hearing thresholds over the first six to 12 weeks,” Dr. Lustig says.
The dual adeno-associated virus (AAV) vector is infused into the inner ear via catheter, a process that takes about 15 minutes.
CHORD Study Results and the Future Impact
The CHORD study is ongoing, and investigators are aiming to enroll up to 30 patients under age 18 with biallelic OTOF variants and profound deafness. Patients are not eligible if they have cochlear implants in both ears, as the implant process damages hair cells and can cause scarring and bone formation that prevents the restoration of hearing. However, if a patient only has an implant in one ear, the other ear can receive the therapy.
In the first results reported from the trial, 12 patients were treated. Nine received the gene therapy infusion in a single ear, and three received infusions in both ears.
At the end of 24 weeks, nine patients were hearing at a level that did not require cochlear implants. Three children achieved normal hearing sensitivity after treatment and six could hear soft speech without assistive devices. Auditory brain-stem response, a key secondary endpoint of the trial, was seen in nine of 12 patients.
The gene therapy was even effective in two of the oldest patients enrolled in the trial, who were 16, suggesting that its use may not be limited to young children.
“Our initial predictions were that only young kids would be really good candidates. And the older you were, the less likely you would respond. But we did have 8-year-olds, 10-year-olds, and teenagers with improved hearing,” Dr. Lustig says.
There are currently five different groups around the world using a similar gene therapy treatment strategy for OTOF-related deafness, and he believes that the recent FDA approval will drive additional interest, funding, and trials to test gene therapies on more common forms of genetic deafness.
Dr. Lustig is also hopeful that the recent advancements will increase newborn genetic testing for hearing loss, which would allow researchers to develop a much better understanding of the individual genetic mutations that affect hearing over time.
“It’s going to put a lot of wind in the sails of everybody working on gene therapy for hearing loss,” he says.
