Pioneering gene therapy has restored hearing in a British baby born with profound genetic deafness, along with other children in China and the US, marking “a new era in deafness treatment”.
The results from different gene therapy trials were released at a US conference from 7 to 11 May 2024 where French company Sensorion announced it would also begin trials of its gene therapy for deafness in 2024.
Six months after a single intracochlear injection delivered via a one-off infusion into British girl Opal Sandy’s right ear, her hearing had ”improved close to normal hearing levels” in the treated ear, doctors told the conference.
At 11 months of age, she was among the world’s youngest to receive gene therapy for deafness after being born with auditory neuropathy due to a variation in the otoferlin gene (OTOF) which produces the protein otoferlin, needed to allow inner hair cells in the ear to communicate with the hearing nerve.
She is taking part in the CHORD trial by Regeneron Pharmaceuticals which aims to determine if the investigational gene therapy DB-OTO can provide hearing for children born with this condition. Regeneron released initial results on 8 May 2024 at the 27th annual meeting of the American Society of Gene and Cell Therapy.
It said results showed “dramatically improved hearing to normal levels” in Opal and initial hearing improvements in another child aged four at a six-week assessment. The ongoing trial is enrolling children in the UK, US and Europe.
Clinicians said they noticed continuous improvement in Opal’s hearing in the weeks after treatment and at 24 weeks post-therapy confirmed close to normal hearing levels for soft sounds, such as whispering, in her treated ear. Now 18 months old, she can respond to her parents’ voices and say some words.
Spectacular results
Professor Manohar Bance, chief investigator of the British trial and ear surgeon at Cambridge University Hospitals NHS Foundation Trust, said in a statement: “These results are spectacular and better than I expected. Gene therapy has been the future in otology and audiology for many years and I’m so excited that it is now finally here. This is hopefully the start of a new era for gene therapies for the inner ear and many types of hearing loss.”
Opal received an infusion containing a harmless virus (AAV1) which delivered a working copy of the OTOF gene via injection in the cochlea of her right ear during surgery. In the same surgery, at Addenbrooke’s Hospital in Cambridge, a cochlear implant was fitted in her left ear.
Bance explained the therapy helps hair cells regrow. He said children with a variation in the OTOF gene often passed newborn screening, as the hair cells were working, but not talking to the nerve. It meant this hearing loss was not commonly detected until children were two or three years of age – when a delay in speech was likely to be noticed.
He added: “We have a short time frame to intervene because of the rapid pace of brain development at this age. Delays in diagnosis can cause confusion for families as the many reasons for delayed speech and late intervention can impact a child’s development.
“More than 60 years after the cochlear implant was first invented – the standard of care treatment for patients with OTOF related hearing loss – this trial shows gene therapy could provide a future alternative. It marks a new era in the treatment for deafness. It also supports the development of other gene therapies that may make a difference in other genetic related hearing conditions, many of which are more common than auditory neuropathy.”
Opal’s mother Mrs Jo Sandy said in a video: “When Opal could first hear us clapping unaided it was mind-blowing – we were so happy when the clinical team confirmed at 24 weeks that her hearing was also picking up softer sounds and speech. The phrase ‘near normal’ hearing was used and everyone was so excited that such amazing results had been achieved.”
Her father Mr James Sandy said: “It was our ultimate goal for Opal to hear all the speech sounds. It’s already making a difference to our day-to-day lives like at bath-time or swimming when Opal can’t wear her cochlear implant. We feel so proud to have contributed to such pivotal findings, which will hopefully help other children and their families in the future.”
Dr Richard Brown, CUH consultant paediatrician and investigator on the CHORD trial added: “It is likely that in the long run such treatments require less follow up so may prove to be an attractive option, including within the developing world. Follow up appointments have shown effective results so far with no adverse reactions and it is exciting to see results to date.”
Follow up will continue for five years to show how patients adapt to understand speech.
Addressing root cause
Clinical trial investigator, Dr Lawrence Lustig, chair of Columbia University’s Department of Otolaryngology – Head and Neck Surgery, presented results from the British children at the conference saying the opportunity of providing the full complexity and spectrum of sound in children born with profound genetic deafness was a phenomenon he did not expect to see in his lifetime.
“These impressive results showcase the revolutionary promise of DB-OTO as a potential treatment for otoferlin-related deafness, and we are excited to see how this translates into an individual’s development, especially since early intervention is associated with better outcomes for speech development,” he said in a statement.
“We’re part of the beginning of a new era of gene therapy research that looks to create treatment options that address the root cause of profound genetic deafness.”
Regeneron said Opal had improvement of hearing to normal levels across key speech frequencies at 16 months of age at the 24-week assessment with an average 84 decibel improvement from baseline and one frequency measure reaching 10dB in hearing level per pure-tone average (PTA.) Across all tested frequencies, an average 80dB improvement from baseline was observed. Auditory brainstem response (ABR) was positive, with best frequency reaching 45dB.
A second participant experienced consistent results to Opal at the six-week assessment including initial improvement of hearing with responses to loud sounds, which was observed across key speech frequencies, with an average 19dB improvement from baseline and one frequency measure reaching 80dB in hearing level per PTA. Across all tested frequencies, an average 16dB improvement from baseline was observed. ABR was positive, with best frequency reaching 75dB.
Other trials
In a trial by Refreshgene Therapeutics, five of six children in China (video of one here) with autosomal recessive deafness 9 received AAV1-hOTOF gene therapy and showed ‘robust hearing improvement’ over 26 weeks. Updated findings (p78-79) released at the conference by researchers from Fudan, China and Harvard Medical School, USA, concluded the therapy was safe and efficacious.
Otolaryngology Associate Professor Zheng-Yi Chen of Massachusetts Eye and Ear Infirmary and Harvard said FDA approval of the therapy could be three to five years away.
“This is truly remarkable. When we tell the story, even for our colleagues, it brings a tear to the eye,” Chen told Harvard Gazette. “I’ve been working in this field for three decades, and I know how difficult it has been to come to this point.”
Akouos also shared data at the conference about its investigational gene therapy AK-OTOF-101 including that in October 2023, an American boy, 11, born profoundly deaf in both ears with OTOF-mediated hearing loss had his hearing improved enough that he now has only mild to moderate hearing loss in the ear that was treated.
More reading
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