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Introduction: Autosomal recessive deafness 9 (DFNB9) is a congenital auditory neuropathy with clinical features including congenital or prelingual, bilateral symmetry, severe to complete deafness, caused by OTOF mutations. We previously reported the safety and efficacy of adeno-associated virus (AAV) mediated OTOF (AAV-OTOF) delivery in children for the first time worldwide. It is believed that AAV-OTOF can restore hearing in infants and children with DFNB9, but there have been no safety and efficacy studies in elder participants. This study enrolled the adolescent and adult participants and aimed to investigate the association of age with safety and efficacy of AAV-OTOF gene therapy. Material and methods: This study is a multicenter, open-label, single-arm and intervention trial. We recruited 9 DFNB9 participants with age diversity (1.8- to 23.9-year-old) from 4 Chinese sites. All participants carry biallelic OTOF mutations with severe to complete hearing loss, unilateral or no cochlear implantation. Participant 3 received two rounds of AAV-OTOF injection. Single injection of AAV-OTOF into the inner ear was performed in other 8 participants. The follow-up period was from July 2023 to May 2024. The primary outcomes were safety and tolerability. Secondary outcomes included auditory function assessments. Results: We present a relevant evaluation of safety and efficacy in 9 participants 2-9 months after AAV-OTOF treatment. No serious adverse events (AEs) occurred in the dose of AAV-OTOF at 8.4 x 1011 to 1.12 x 1012 vg. No serious drug-related AEs (AEs) were observed with a total number of 8 of grade I and II AEs. Hearing recovered in 8 participants after surgery. At 1 month after surgery, the mean click ABR threshold for participants decreased from >99 dB at baseline to 56.7 dB. Notably, the thresholds of click-ABR, tone-burst ABR (TB-ABR) and pure tone audiology (PTA) thresholds for the 23.9-year-old adult participant decreased from >100 dB, >100 dB, and 93.6 dB at baseline to 70, 81, 67.9 dB at 1 month, respectively. We found that the hearing recovery effects showed a potential age correlation. Participants with hearing recovery were divided into three groups by age (1: 1-2 years; 2: 5-8 years; 3: >14 years). The thresholds of click-ABR (PTA) in the 3 groups were improved by 45 dB (7.9 dB), 51.8 dB (56.7 dB) and 20 dB (25.7 dB) at 1 month, respectively. The thresholds of TB-ABR in group 2 and 3 improved from >99 dB at baseline to 57 dB and 69 dB at 1 month, respectively. Overall, participants aged 5-8 years had a better hearing recovery. Conclusions: In this trial, AAV-OTOF gene therapy was proved as a safe and effective treatment for infants to adult patients with DFNB9, which appears to be age-related therapeutics and indicated a large treatment window of AAV mediated gene therapy. [ABSTRACT FROM AUTHOR]