World-first trial to provide hearing for children with rare type of genetic hearing loss launches in Cambridge

Addenbrooke’s Hospital in Cambridge is participating in a world-first trial to see whether gene therapy can provide hearing for children with severe to profound hearing loss due to a rare genetic condition.

The trial supported by the NIHR Cambridge BRC and NIHR Cambridge Clinical Research Facility, aims to show whether gene therapy can provide hearing for children born with hearing loss due to auditory neuropathy, a condition caused by the disruption of nerve impulses travelling from the inner ear to the brain.

Up to 18 children under the age of 18 years from three participating countries – the UK, Spain and the USA – will be included in the trial and followed up for five years to see the extent to which their hearing improves.

Auditory neuropathy can be due to a variation in a single gene – known as the OTOF gene – which produces a protein called otoferlin.  This protein typically allows the inner hair cells in the ear to communicate with the hearing nerve.  Mutations in the OTOF gene can be identified by standard NHS genetic testing. 

About 20,000 people across the US and EU5 (UK, Germany, France, Spain and Italy) are thought to have auditory neuropathy due to OTOF mutations.  Children with profound hearing loss face barriers developing communication skills and may miss developmental milestones if the right support is not provided from the start.

Professor Manohar Bance, pictured left, an ear surgeon at Cambridge University Hospitals NHS Foundation Trust, and the chief investigator for the trial said: “Children with a variation in the OTOF gene are born with severe to profound hearing loss, but they often pass the new-born hearing screening so everyone thinks they can hear.  The hair cells are working, but they are not talking to the nerve.

“Gene therapy for otoferlin deficiency is the right starting point for young children because it’s among – if not the most – simple approaches for treating hearing loss; everything else should be intact and working normally.  Although experimental, the therapy could also potentially result in better quality hearing compared to cochlear implants.  But we have a short time frame to intervene because the young brain is developing so fast.” 

Intervening later in life becomes less effective as children may never fully form the ability to process the sounds of speech.  If successful for OTOF related hearing loss, gene therapy treatments could be extended to include people with hearing loss due to other more common genetic conditions.  

“It’s really important that we get the first gene therapy treatment right because it will allow us to proceed to treating other genetic conditions,” added Professor Bance.

Gene therapy aims to deliver a working copy of the faulty OTOF gene using a modified, non-pathogenic virus.  It will be delivered via an injection into the cochlea during surgery under general anesthesia. The procedure is similar to cochlear implant surgery, the current standard of care for OTOF related hearing loss.

The trial will consist of three parts, which must be done in order, with children receiving:

1. A starting dose of gene therapy (DB-OTO) in one ear only.
2. A higher dose of gene therapy in one ear only, following proven safety of the starting dose.
3. Gene therapy in both ears with the optimal dose selected after ensuring the safety and effectiveness of DB-OTO in parts 1 and 2.

If the gene therapy is not effective for a child 6 months after treatment, the family can choose to receive a cochlear implant in the treated ear(s).

Ralph Holme, Director of Research and Insight at RNID said:“At RNID we are committed to a future where effective treatments for hearing loss are available for those who need and want them. Gene therapies have the potential to offer long lasting and permanent treatments for hearing loss, rather than merely managing the symptoms as hearing aids do. We welcome this pioneering trial, which we hope will lead to a treatment for children with OTOF related hearing loss and pave the way towards treatments for other genetic conditions.”

Martin McLean, Senior Policy Advisor at the National Deaf Children’s Society, said: “This is a significant development that will be of great interest to families of deaf children whose deafness is caused by a variation in the OTOF gene. The trial will help us to understand more about the effectiveness of gene therapy in improving hearing where deafness has a specific genetic cause.

“While some families will welcome being able to access this trial, it should be emphasised that with the right support from the start, deafness is not a barrier to achievement or happiness. Our role is to support families to make informed choices on whether they want to take up new treatments like this one which have the potential to mitigate the challenges their child might face.”

The trial is sponsored by Decibel Therapeutics, a Boston, US-based company specialising in gene therapies for hearing and balance disorders. DB-OTO is being developed by Decibel Therapeutics in collaboration with Regeneron Pharmaceuticals, Inc. It is supported by the National Institute for Health and Care Research (NIHR) Cambridge Clinical Research Facility and NIHR Cambridge Biomedical Research Centre.

Professor Bance also runs a multidisciplinary genetic hearing loss clinic to help improve the treatment and care of children with hearing disorders. These are examples of services that could be offered at the new Cambridge Children’s Hospital currently in planning.

All clinical trials that take place at Cambridge University Hospitals NHS Foundation Trust (CUHFT) are independently assessed for safety and quality by the Health Research Authority and Research Ethics Committee and complete the required legal and regulatory approvals before CUHFT agrees to participate. A team at the hospital has reviewed the safety protocols and all the necessary information; the trial will be performed and monitored by an experienced team of doctors, nurses and clinical support staff. All participating families give informed consent before treatment.

For more information about the CHORD clinical trial (NCT0578836), including eligibility criteria, please visit: Study Record | ClinicalTrials.gov