A recent breakthrough in the field of gene therapy offers hope to individuals affected by congenital deafness, a condition affecting around 26 million people worldwide, with up to 60% of cases attributed to genetic mutations. Autosomal recessive deafness 9 (DFNB9), a specific type characterized by severe-to-complete, congenital or prelingual, bilateral hearing loss, is linked to dysfunction of the otoferlin gene (OTOF), accounting for 2-8% of congenital deafness cases.
Researchers at the Eye & ENT Hospital of Fudan University in Shanghai, China, conducted a groundbreaking clinical trial focusing on gene therapy for DFNB9. The trial, published in The Lancet, is the first of its kind, demonstrating successful restoration of hearing in children with hereditary deafness. MMed et al. evaluated the safety and effectiveness of gene therapy using an adeno-associated virus (AAV) serotype 1 carrying a human OTOF transgene (AAV1-hOTOF) and investigated it as a treatment for children with DFNB9. This single-arm, single-center trial enrolled children aged between 1 to 18 years with severe-to-complete hearing loss and confirmed mutations in both alleles of OTOF but without bilateral cochlear implants. A single injection of AAV1-hOTOF was administered into the cochlea via the round window. The primary endpoint of the study was to assess dose-limiting toxicity at 6 weeks after injection. The efficacy of the therapy was assessed using appropriate auditory perception evaluation tools to measure auditory function and speech. All analyses were performed according to the intention-to-treat principle.
The study results are exceptionally promising, revealing significant improvements in the hearing abilities and speech recovery of the six children enrolled in the trial. The participants, who suffered from total deafness due to DFNB9, were treated with an adeno-associated virus (AAV) carrying a version of the human OTOF gene. The AAV was carefully introduced into the inner ears through a specialized surgical procedure. Over the 26-week observation period, five out of six children exhibited remarkable hearing recovery, with a 40-57 decibel reduction in auditory brainstem response (ABR) testing, substantial enhancements in speech perception, and the restored ability to engage in normal conversation. Importantly, no dose-limiting toxicity was observed, and the adverse events recorded were mostly low-grade and transitory.
The study sheds light on the potential of gene therapies as a viable solution for hereditary deafness, which currently lacks FDA-approved drugs. The trial success also emphasizes the effectiveness of using a dual-AAV vector, which carries two pieces of the OTOF gene. This vector overcomes the conventional gene size limit associated with AAVs. The study highlights the potential to expand gene therapy treatments to address various forms of genetic hearing loss.
Reference
Lv J, Wang H, Cheng X, Chen Y, Wang D, Zhang L, et al. AAV1-hOTOF gene therapy for autosomal recessive deafness 9: a single-arm trial. The Lancet [Internet]. 2024 Jan 24 [cited 2024 Jan 29];0(0).