Results of a gene therapy trial have been labelled “astounding”, raising hopes for future treatment after five children who were born deaf now have hearing in both ears, just weeks after their participation.
The children were unable to hear because of inherited genetic mutations that disrupt the body’s ability to make a protein needed to ensure auditory signals pass seamlessly from the ear to the brain, reports The Guardian.
Doctors at Fudan University in Shanghai treated the children, aged between one and 11, in both ears in the hope they would gain sufficient 3D hearing to take part in conversations and work out from which direction sounds were coming.
Within weeks of receiving the therapy, the children had gained hearing, could locate the sources of sounds, and recognised speech in noisy environments. Two of the children were recorded dancing to music, the researchers reported in Nature Medicine.
Dr Zheng-Yi Chen, a scientist at Massachusetts Eye and Ear, a Harvard teaching hospital in Boston that co-led the trial, said the results were “astounding”, adding that researchers continued to see the children’s hearing ability “dramatically progress”.
The therapy uses an inactive virus to smuggle working copies of the affected gene, Otof, into the inner ear. Once inside, cells in the ear use the new genetic material as a template to churn out working copies of the crucial protein, otoferlin.
Video footage of the patients shows a two-year-old boy responding to his name three weeks after the treatment and dancing to music after 13 weeks, having shown no response to either before receiving the injections.
Another patient, a three-year-old girl, fails to react to sounds, but 13 weeks after the treatment can understand sentences and speak some words.
The oldest patient, an 11-year-old girl, showed no response to tones played at various pitches before the therapy, but reacted to all of them six weeks later and was able to take part in speech training from the 13-week mark.
More than 430m people globally are affected by disabling hearing loss, of whom about 26m are deaf from birth.
Up to 60% of childhood deafness is due to genetic factors. The children in the trial have a condition called DFNB9, caused by Otof mutations, which accounts for 2%-8% of all congenital hearing loss.
In January, the same US-Chinese team reported improvements after treating the deaf children in one ear, but the intention was always to give hearing in both ears.
If they can hear in both ears, the children can work out where sounds are coming from, a capability important for everyday situations such as talking in groups and being aware of traffic when crossing the road, the researchers said.
They said it will take larger trials to assess the benefits and risks of the therapy in more detail.
The gene therapy is injected during a minimally invasive surgical procedure, so treating both ears doubles the time that patients spend in surgery. Treating both ears also raises the risk of a stronger immune reaction, triggered when the body’s defences react to the virus that delivers the therapy.
“Our hope is this trial can expand and this approach can also be looked at for deafness caused by other genes or non-genetic causes,” Chen said. “Our ultimate goal is to help people regain hearing no matter how their hearing loss was caused.”
Last month, a British toddler became the first person to have her hearing restored in one ear after receiving a similar gene therapy for hearing loss caused by Otof mutations.
Prof Manohar Bance, the chief investigator on that trial, said the therapy marked a new era in the treatment of deafness.
Study details
Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results
Hui Wang, Yuxin Chen, Jun Lv et al.
Published in Nature Medicine on 5 June 2024
Abstract
Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five paediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings.
The Guardian article – Gene therapy trial gives deaf children hearing in both ears (Open access)
See more from MedicalBrief archives:
Gene therapy restores child’s hearing, stimulates speech
Gene therapy restores hearing in children with hereditary deafness
Quicker test being trialled to help prevent permanent deafness in babies