Gene Therapy For Auditory Neuropathy

 by Natalie M

Auditory neuropathy is a disorder where the ear detects sound successfully but has an issue with sending auditory information from the ear to the brain. This can allow hearing to be unaffected or result in hearing loss of varying degrees. However, it always results in poor speech-perception abilities - so those with the condition find difficulty in understanding speech clearly. This may be caused by damage to the inner ear hair cells that receive information about sounds to be transmitted through the nervous system to the brain or by damage to auditory neurons actually transmitting the information. In Opal Sandy’s case, it is due to inheritance of faulty genes.

Auditory neuropathy can be attributed to a variation in the OTOF gene. This gene produces a protein, otoferlin, which is needed to allow the inner hair cells in the ear to communicate with the hearing nerve. However, the variation prevents the production of otoferlin. The inner ear hair cell synapses encode both the frequency content and intensity fluctuations of sound and transmit the information to spiral ganglion neurons with precision. Otoferlin is important in this synaptic transmission by tethering synaptic vesicles to the plasma membrane, by its presumed function as a Ca2+ sensor. Inner ear hair cell function and sound encoding appear to be directly related to the amount of plasma membrane otoferlin. Once this amount is reduced, as it is in OTOF patients, synaptic sound encoding is compromised, leading to hearing loss.

Because the hair cells are working, children with a variation in the OTOF gene pass newborn screenings and this leads to hearing loss being undiagnosed for 2-3 years (until delays in speech are noticeable). Opal was identified with the variation earlier (due to her sister having the same condition) at 3 just weeks old. 

The CHORD trial, sponsored by Regeneron, started in May 2023 and aims to show whether gene therapy can provide hearing for children born with auditory neuropathy. The study currently has enrolled patients in the UK, Spain and the US.

The patient is given an infusion containing AAV1 (a harmless virus). It delivers a functional copy of the OTOF gene via an injection in the cochlear, in surgery under general anaesthetic. This way, cells produce otoferlin and synaptic transmission is greatly improved. Due to the injection being limited to the cochlear, as opposed to the entire body, the risk of side effects is greatly reduced making this treatment a particularly viable option for younger patients.

In the first phase of the study a low dosage is given to one ear only. A higher dosage may be used in the second phase in the same ear, if the first dosage’s safety has been proven, and the third phase will take into account treating both ears with gene therapy. To further understand the impact of the gene therapy, patients will have follow-up appointments for 5 years to observe how they adapt to understand speech in the long term.

Opal is the first patient in Britain and the youngest globally to receive this treatment and it has yielded incredible results. She was given gene therapy in the right ear and a cochlear implant in the left ear. Her case exemplifies the significance of early treatment - due to the short time frame for intervention due to the rapid development of the brain at younger ages. Within 4 weeks of the gene therapy infusion to her right ear, Opal responded to sound - even with the cochlear implant in her left ear switched off.

Furthermore, at 24 weeks she has close to normal hearing levels for soft sounds in the treated ear - such as whispering. At 18 months old currently, Opal can respond to her parents' voices by calling out to them and saying ‘bye-bye’ verbally, already demonstrating massive improvements to her speech-perception abilities.