Seven children around the globe, once profoundly deaf from mutations in the otoferlin (OTOF) gene, have regained much of their hearing from gene therapy, according to preliminary results from multiple early-stage clinical trials. As a person with a progressive, genetic hearing loss, and as a strategy consultant specializing in hearing healthcare, I view the data from these early-stage clinical trials as deeply hopeful.
What we found was that the patients’ treated ears are no longer indicated for a cochlear implant, only a hearing aid. Restoring hearing to the point where a child no longer requires a surgically-administered cochlear implant has tremendous benefits. Yet if some patients continue to require hearing aids after undergoing gene therapy, providers and payers must address chronic barriers in pediatric hearing healthcare to realize the promise of gene therapy for hearing loss.
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Before proceeding, I want to acknowledge that some parents believe that their child’s hearing loss should not be treated. Many members of the Deaf community view deafness as an integral part of a child’s identity, not a shortcoming that requires fixing.
Analyzing the clinical trial results
We analyzed the published audiograms and other reported data from three separate clinical trials targeting the OTOF gene, using hearing impairment grades established by the World Health Organization. An audiogram plots the softest sound a patient can hear in decibels, for a specific set of tones increasing in pitch, or frequency.
In all three of these clinical trials, an ear surgeon infused gene therapy into the entrance of the patients’ cochlea, or inner ear. Once inside the ear, the transgene created the missing otoferlin protein, necessary for the cells in the cochlea to transmit sound to the brain.
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The clinical trial results we analyzed are:
- One 12-week post-treatment audiogram. The patient was 10-months old at the time of receiving DB-OTO gene therapy. Regeneron shared these results in January at the JP Morgan Healthcare Conference for their recently acquired unit, Decibel Therapeutics (read editor’s note below). The clinical trial site was Cambridge University Hospital in the United Kingdom, with the primary investigator Professor Manohar Bance, M.B..
- Five 26-weeks post-treatment audiograms. Results for five children were published in The Lancet for a clinical trial held in China, at Fudan University’s Eye & ENT Hospital and sponsored by Shanghai Refresh Gene Therapeutics. Dr. Zheng-Yi Chen of Massachusetts Eye and Ear co-leads the study.
- One 30-day post-treatment partial audiogram. The results shared a few frequencies for an 11-year old treated by Professor John Germiller, M.D., Ph.D., the principal investigator of the AK-OTOF-101 Clinical Trial at Children’s Hospital of Philadelphia. Akouos, a biotech startup in hearing loss owned by Eli Lilly, sponsors this study (read editor’s note below).
These seven children entered clinical trials diagnosed with a profound hearing loss, unable to hear a shouted voice directly into the ear. One to six months after treatment, five of the children’s treated ears now registered a moderate hearing loss, meaning that they would have difficulty hearing only a soft voice about three feet away. A sixth child’s treated ear had a moderately-severe loss, translating to difficulty hearing a normal voice at the same distance.
In these six cases, which are nothing short of miraculous, the treated ears went from being indicated for a cochlear implant to only a hearing aid. While Akouos’ press release did not contain a full audiogram, our analysis indicates that the patient’s average level across the frequency thresholds could require a hearing aid to reach normal levels on an audiogram.
Interpreting the clinical trial results
The preliminary clinical trial data suggests that some patients who undergo gene therapy for hearing loss may continue to require hearing aids. Unlike cochlear implants, hearing aids do not require surgery under general anesthesia, with its attendant surgical risks that, although low, still exist. Hearing aids cost a fraction of cochlear implants.
Moreover, people who wear hearing aids comprehend and enjoy music more easily. That’s because cochlear implants replace the inner ear’s work–by transforming sound with its mechanical vibrations into electrical impulses understood by the brain–while hearing aids simply boost the inner ear’s work by providing amplified sound. Not surprisingly, the human ear is far more adept at processing music than its mechanical equivalent. As as an ardent pianist who happens to have hearing loss, I find any opportunity for my community to savor music especially moving.
Currently, parents with babies and children with diagnosed hearing loss face a number of barriers to treatment. Hospitals, providers, and payers would benefit from better understanding and addressing these gaps in care.
The role of hearing healthcare in gene therapy
Any infant who fails newborn hearing screening should undergo diagnosis before three months of age, instructs the 2019 Joint Committee On Infant Hearing (JCIH) Position Statement. Once diagnosed, “the child and family should have immediate access, through their audiologist, to high-quality, well-fitted, and optimized hearing aid technology.” Time is of the essence for a child to develop language, “for optimal cognitive, emotional, and educational development.”
The patient in the Akouos trial demonstrates the necessity of hearing for language development. Aged eleven when he underwent the gene therapy treatment for OTOF mutations, he can now hear people’s voices and sounds in his environment, yet most likely will not learn to speak. Instead, he will continue to rely on sign language to communicate. That’s because the brain forms the connections needed to comprehend language generally in the first three years of life.
Yet infants whose newborn hearing screening indicates possible hearing loss are not diagnosed until they are almost 10 months old on average, according to an important study by Lisa Zhang of children who were fitted for hearing aids at a large urban tertiary care center. Moreover, an additional six months elapses before children are fitted with hearing aids. While the interval between newborn hearing screening and receiving hearing aids was less than 16 months for children with more severe hearing loss, the study also indicates that it widens considerably for children with non-white ethnicity.
The pediatric audiologists I have met in my work are dedicated and hardworking. Yet hearing healthcare has a persistent shortage of qualified pediatric audiologists. Causes of this shortage include “a low emphasis on infant audiology practices in audiology training programs, poor reimbursement rates for time-intensive infant hearing evaluations … and the necessity for specialized equipment,” as outlined in an excellent article by Caitlin Sapp in 2021 in the American Journal of Audiology.
The lack of qualified audiologists also creates backlogs in fitting children with hearing aids. A proper fitting includes programming the aids to the profile of the child’s loss and shape of the physical ear canal. Children need regular hearing tests, since their hearing can fluctuate or deteriorate, requiring the audiologist to reprogram hearing aids. Ideally, pediatric audiologists also make time to counsel the family on how to advocate for the child’s needs, an essential yet difficult task given the demands on their time.
Conclusion
The preliminary results from three clinical trials administering gene therapy to address deafness from otoferlin mutations mark inspiring and incredible progress in hearing healthcare. The early data suggests that some children who undergo gene therapy will still be indicated for hearing aids. To fully realize benefits from gene therapy, hearing healthcare will need to address long standing structural barriers in diagnosing infants with hearing loss and fitting them with hearing aids.
Editor’s Note: The author has advised Decibel Therapeutics on physician and patient needs for gene therapy and on developing a genetic testing strategy. She has also consulted with Akouos on the patient journey and advocacy strategy.
Photo: Naeblys, Getty Images
