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Gene therapy restores hearing in children with hereditary deafness

Scientists have been able to effectively use gene therapy to restore hope and hearing to children suffering from hereditary deafness – the first human clinical trial to administer the therapy for treating this condition.

Co-led by investigators from Mass Eye and Ear, a member of Mass General Brigham, the trial of six children took place at the Eye & ENT Hospital of Fudan University in Shanghai, China, during which the researchers found the novel gene therapy to be effective for patients with a specific form of autosomal recessive deafness caused by mutations of the OTOF (otoferlin) gene, called DFNB9.

With its first patient treated in December 2022, this research represents the first human clinical trial to administer gene therapy for treating this condition, with the most patients treated and the longest follow-up to date.

Their results were published in The Lancet.

“If children are unable to hear, their brains can develop abnormally without intervention,” said Zheng-Yi Chen, DPhil, an associate scientist in the Eaton-Peabody Laboratories at Mass Eye and Ear and associate professor of Otolaryngology – Head and Neck Surgery at Harvard Medical School. “The results from this study are truly remarkable. We saw the hearing ability of children improve dramatically week by week, as well as the regaining of their speech.”

MedicalXpress reports that hearing loss affects more than 1.5bn people worldwide, with congenital deafness making up about 26m of those. For hearing loss in children, more than 60% have a genetic cause.

DFNB9 for example, is a hereditary disease caused by mutations of the OTOF gene and a failure to produce a functioning otoferlin protein, which is necessary for the transmission of the sound signals from the ear to the brain.

There are currently no FDA-approved drugs to help with hereditary deafness, which has opened the door for new solutions like gene therapies.

To test this novel treatment, six children with DFNB9 were observed over a 26-week period at the Eye & ENT Hospital of Fudan University. The Mass Eye and Ear collaborators utilised an adeno-associated virus (AAV) carrying a version of the human OTOF gene to carefully introduce the gene into the inner ears of the patients through a special surgical procedure.

Differing doses of the single injection of the viral vector were used.

All six children had total deafness, as indicated by an average auditory brainstem response (ABR) threshold of more than 95 decibels. After 26 weeks, five children demonstrated hearing recovery, showing a 40–57 decibel reduction in ABR testing, dramatic improvements in speech perception and the restored ability to conduct normal conversation.

Overall, no dose-limiting toxicity was observed. While following up on the patients, 48 adverse events were observed, with a significant majority (96%) being low grade, and the rest being transitory with no long-term impact.

The study provides evidence of the safety and effectiveness of gene therapies in treating DFNB9, as well as their potential for other forms of genetic hearing loss. Moreover, the results contribute to an understanding of the safety of AAV insertion into the human inner ear.

In regard to the usage of AAVs, the success of a dual-AAV vector carrying two pieces of the OTOF gene is notable. Typically, AAVs have a gene size limit, and so for a gene like OTOF that exceeds that limit, the achievement with a dual viral vector opens the door for AAVs use with other large genes that are typically too big for the vector.

“We are the first to initiate the clinical trial of OTOF gene therapy. It is thrilling that our team translated the work from basic research in animal model of DFNB9 to hearing restoration in children with DFNB9,” said lead study author Yilai Shu, MD, of the Eye & ENT Hospital of Fudan University.

The researchers plan to expand the trial to a larger sample size as well as track their outcomes over a longer timeline.

“Not since cochlear implants were invented 60 years ago has there been an effective treatment for deafness,” said Chen. “This is a huge milestone that symbolises a new era in the fight against all types of hearing loss.”

Study details

AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial

Jun Lv,  Hui Wang, Xiaoting Cheng,  Yuxin Chen, Daqi Wang, Longlong Zhang, et al.

Published in The Lancet on 24 January 2024


Autosomal recessive deafness 9, caused by mutations of the OTOF gene, is characterised by congenital or prelingual, severe-to-complete, bilateral hearing loss. However, no pharmacological treatment is currently available for congenital deafness. In this article, we report the safety and efficacy of gene therapy with an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) as a treatment for children with autosomal recessive deafness 9.

This single-arm, single-centre trial enrolled children (aged 1–18 years) with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF, and without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea through the round window. The primary endpoint was dose-limiting toxicity at 6 weeks after injection. Auditory function and speech were assessed by appropriate auditory perception evaluation tools. All analyses were done according to the intention-to-treat principle. The trial is ongoing.

Between 19 October 2022, and J9 une 2023, we screened 425 participants for eligibility and enrolled six children for AAV1-hOTOF gene therapy (one received a dose of 9 × 1011 vector genomes [vg] and five received 1·5 × 1012 vg). All participants completed follow-up visits up to week 26. No dose-limiting toxicity or serious adverse events occurred. In total, 48 adverse events were observed; 46 (96%) were grade 1–2 and two (4%) were grade 3 (decreased neutrophil count in one participant). Five children had hearing recovery, shown by a 40–57 dB reduction in the average auditory brainstem response (ABR) thresholds at 0·5–4·0 kHz. In the participant who received the 9 × 1011 vg dose, the average ABR threshold was improved from greater than 95 dB at baseline to 68 dB at 4 weeks, 53 dB at 13 weeks, and 45 dB at 26 weeks. In those who received 1·5 × 1012 AAV1-hOTOF, the average ABR thresholds changed from greater than 95 dB at baseline to 48 dB, 38 dB, 40 dB, and 55 dB in four children with hearing recovery at 26 weeks. Speech perception was improved in participants who had hearing recovery.

AAV1-hOTOF gene therapy is safe and efficacious as a novel treatment for children with autosomal recessive deafness 9.


The Lancet article – AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial (Open access)


MedicalXpress article – Gene therapy restores hearing in children with hereditary deafness (Open access)


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