The guest editor of a forthcoming supplement for ENT & Audiology News has helped enable a baby girl born deaf to hear unaided for the first time. Professor Manohar Bance, an ear surgeon at Cambridge University Hospitals NHS Foundation Trust, UK, is the chief investigator of the ground-breaking gene therapy trial. 

“These results are spectacular and better than I expected,” said Prof Bance, who is guest editing the magazine’s Implantation Otology and Inner Ear Therapeutics supplement in July. “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 Sandy from Oxfordshire is the first patient treated in a global gene therapy trial, which shows “mind-blowing” results. She is the first British patient in the world and, at eleven months, was the youngest child to receive this type of treatment. 

Opal was born completely deaf because of a rare genetic condition, auditory neuropathy, caused by the disruption of nerve impulses travelling from the inner ear to the brain. 

Within four weeks of having the gene therapy infusion to her right ear at Addenbrooke’s Hospital in Cambridge, Opal responded to sound, even with the cochlear implant in her left ear switched off. 

Clinicians noticed continuous improvement in Opal’s hearing in the weeks afterwards and at 24 weeks confirmed close to normal hearing levels for soft sounds, such as whispering, in her treated ear. 

Now 18 months old, Opal can respond to her parents’ voices and can communicate words such as “dada” and “bye-bye.” 

Opal's mother, Jo Sandy, said: “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 such amazing results had been achieved. 

Auditory neuropathy can be due to a variation in a single gene, known as the OTOF gene. The gene produces a protein called otoferlin, needed to allow the inner hair cells in the ear to communicate with the hearing nerve. Approximately 20,000 people across the UK, Germany, France, Spain, Italy and UK and are deaf due to a mutation in the OTOF gene. 

The CHORD trial, which started in May 2023, aims to show whether gene therapy can provide hearing for children born with auditory neuropathy. 

Children with a variation in the OTOF gene often pass the newborn screening, as the hair cells are working, but they are not talking to the nerve. It means this hearing loss is not commonly detected until children are 2 or 3 years old – when a delay in speech is likely to be noticed. 

Prof Bance added: “We have a short time frame to intervene because of the rapid pace of brain development at this age. Delays in the diagnosis can also cause confusion for families as the many reasons for delayed speech and late intervention can impact a children’s development. 

“More than 60 years after the cochlear implant was 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 prove to make a difference in other genetic related hearing conditions, many of which are more common than auditory neuropathy.” 

Mutations in the OTOF gene can be identified by standard NHS genetic testing. Opal was identified as being at risk as her older sister has the condition; this was confirmed by genetic test result when she was three weeks old. 

Opal was given an infusion containing a harmless virus (AAV1). It delivers a working copy of the OTOF gene via an injection in the cochlea during surgery under general anaesthesia. During surgery, while Opal was given the gene therapy in right ear, a cochlear implant was fitted in her left ear.  

Dr Richard Brown, Consultant Paediatrician at CUH and Investigator on the CHORD trial, said: "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 the results to date. 

"Within the new planned Cambridge Children’s Hospital, we look forward to having a genomic centre of excellence which will support patients from across the region to access the testing they need, and the best treatment, at the right time.” 

The CHORD trial is sponsored by Regeneron. Patients are being enrolled in the study in the US, UK and Spain. It is one of several ongoing gene therapy studies across the world using the OTOF gene, though the surgical and delivery methods are unique. 

Patients in the first phase of the study receive a low dose to one ear. The second phase are expected to use a higher dose of gene therapy in one ear only, following proven safety of the starting dose. The third phase will look at gene therapy in both ears with the dose selected after ensuring the safety and effectiveness in parts one and twp. Follow up appointments will continue for five years for enrolled patients, which will show how patients adapt to understand speech in the longer term. 

In Cambridge, the trial is supported by NIHR Cambridge Clinical Research Facility and NIHR Cambridge Biomedical Research Centre. 

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