NEW YORK – Five children in China born with severe deafness have exhibited signs of restored hearing after receiving a gene therapy, according to an interim analysis of clinical trial results published Wednesday.
There are multiple clinical trials evaluating gene therapy for this rare type of congenital hearing loss caused by mutations in the OTOF gene, including studies sponsored by Eli Lilly and Regeneron, marking a potential first step into genetic medicines for hereditary deafness. However, new study results published in Nature Medicine represent the first clinical trial to administer a gene therapy to children with OTOF-related deafness in both ears.
In a previous paper, published in the Lancet in January, the same research team reported that five of six patients in China treated with the gene therapy in a single ear experienced improvements in hearing and speech, with no serious adverse events.
Based on those safety and efficacy results, investigators were able to amend the study protocol in July 2023 to allow a new cohort of patients to get the bilateral gene therapy.
Yilai Shu, a professor and director of the diagnosis and treatment center of genetic hearing loss affiliated with the Eye & ENT Hospital of Fudan University and senior study author of the paper, noted that the researchers hoped that administering the experimental treatment to both ears would lead to greater gains in hearing function.
There aren't any pharmaceutical treatments available for hereditary deafness, with typical care comprising assistive support such as cochlear implants.
All five patients enrolled in this trial had severe-to-complete hearing loss before treatment, and none had a cochlear implant.
The ongoing clinical trial is a collaboration between researchers at the Eye & ENT Hospital of Fudan University in Shanghai and Mass General Brigham's Massachusetts Eye and Ear in Boston. This research team developed the gene therapy with support from Shanghai Refreshgene Therapeutics.
As part of this latest single-arm clinical trial investigating safety and efficacy, Shu administered the gene therapy to five children at the Eye & ENT Hospital of Fudan University, who received the treatment in both ears. The therapy, which is injected into the inner ear during a minimally invasive surgery, uses an adeno-associated virus (AAV) vector to deliver functional copies of an OTOF transgene.
The first patient was treated in July of last year. The first three treated patients have completed a 26-week assessment, and the following two patients have completed a 13-week assessment.
The five patients exhibited signs of restored hearing after receiving the gene therapy, with investigators observing improvements in both ears, though they did not reach a normal level of hearing. Patients also experienced additional benefits compared to previous trials, according to the study authors.
For example, at their latest follow-up visit, all five of the patients were able to determine from what direction sounds originated and were able to hear in noisy environments. Most of the patients gained speech capabilities and were able to say simple words. Investigators also said they observed two of the younger children who had 26 weeks of follow-up dancing to music, which they considered a signal of the patients' ability to hear more complex sounds.
"Due to the young age and short follow-up, more detailed evaluation is needed during subsequent follow-up visits," investigators wrote in the paper.
Being able to identify the source of a sound, in particular, plays a role in safety in addition to being a mark of improved hearing.
"You cross a road, you hear a 'beep,'" Zheng-Yi Chen, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear and co-senior study author of the paper, offered as an example. "You can turn to where the sound is coming from."
Not all of the children achieved the same level of hearing improvement. The second patient, who was treated at 1 year old, had a more modest hearing recovery, according to the investigators. However, "interestingly, patient 2 regained the capability of sound source localization, suggesting that even a modest hearing improvement in auditory function was sufficient to reconstitute" this ability, they wrote.
The first patient had greater-than-expected gains in auditory and speech functions. She was 11 years old with no response to sound nor ability to speak before treatment, and was administered the gene therapy before the study was allowed to recruit younger children. Since then, children treated have been 1 to 3 years of age.
The 11-year-old patient achieved improvements in hearing as well as limited speech capacity, including an ability to say words with simple syllables. That's a remarkable improvement, Chen noted, given how much of language development is thought to take place by 6 or 7 years of age.
"She still gained some sort of very rudimentary language," Chen said. "This wasn't expected in the field."
Investigators will continue to monitor her and other patients to see if hearing and speech functions continue to improve.
Safety is a key outcome that investigators are watching in the trial. Since physicians are injecting two doses of AAVs into the body across the two ears, it's possible that some patients could experience a stronger immune response which could lead to more adverse events. On the other hand, injection of the gene therapy into both ears during a single operation may be necessary, since patients who receive an AAV gene therapy in one ear may not be able to receive another dose later on due to anti-AAV neutralizing antibodies. When tested six weeks after treatment, anti-AAV neutralizing antibodies had increased from baseline in all patients.
So far, there have been no serious adverse events nor dose-limiting toxicities.
There have been 36 adverse events in total, all of which were grade 1 or 2, and the most common of which were increased lymphocyte counts and increased cholesterol levels.
The clinical trial is ongoing, and investigators will continue to track patients to confirm safety and efficacy findings.
Shu and Chen are also exploring options to expand the patient population that can receive gene therapy. Shu previously trained under Chen as a postdoctoral fellow at Mass Eye and Ear, and the two researchers have continued to collaborate after Shu returned to Shanghai more than a decade ago. They're exploring treating adult patients with this condition, as well as developing gene therapies for inherited forms of deafness caused by other genetic mutations.
Next, the investigators hope to expand the clinical trial for OTOF-related hearing loss internationally, including in the US.
"We want to have this approach to be used worldwide," Chen said.