Re-administration of AAV-mediated gene therapy for OTOF-related deafness: a single-arm trial.

Authors

Xintai Fan, Longlong Zhang, Ziwen Gao, Lei Han, Ping Yang, Daqi Wang, Hongbing Yu, Qi Cao, Luoying Jiang, Xiaoyun Chen, Xin Zhang, Xiaoting Cheng, Liheng Chen, Jiake Zhong, Jun Lv, Wei Wang, Liling Dai, Ziyi Zhou, Linjie Shi, Yuxin Chen, Biyun Zhu, Shaowei Hu, Honghai Tang, Zheng-Yi Chen, Wuqing Wang, Bing Chen, Huawei Li, Yilai Shu

Published in

Nature medicine. Jun 26, 2026. Epub Jun 26, 2026.

Abstract

Re-administration of adeno-associated virus (AAV)-mediated gene therapy remains challenging due to neutralizing antibodies (NAbs) induced by the initial dose. We previously conducted a single-arm trial showing that single-dose administration of AAV-hOTOF gene therapy in individuals with OTOF-related deafness is safe and leads to hearing improvements. Here we initially demonstrate that AAV1-hOTOF re-administration to the contralateral ear in Otof^-/- mice with peak serum NAb titers successfully rescued hearing with limited immune activation. After a protocol amendment of our trial, four patients (aged 2.2-3.4 years) with pre-existing NAbs (titers 1:135-1:3,645), who had previously received a single dose of the gene therapy, were enrolled to receive a second dose in the contralateral ear, as part of the ongoing trial, with a follow-up ranging from 26 weeks to 52 weeks. The primary endpoint was the occurrence of dose-limiting toxicities at 6 weeks and secondary endpoints included safety and auditory function. No dose-limiting toxicity occurred within 6 weeks. In the secondary outcomes, the 26-week average auditory brainstem response threshold in the second treated ear improved from >95 dB at baseline to 43 dB, 63 dB, 80 dB and 53 dB in patients 1-4, respectively. Safety assessment showed that all adverse events were grade 1-2, except one grade 3 decreased neutrophil count; no serious adverse events occurred. These data provide preliminary insights on the safety and efficacy of re-administration of AAV1-hOTOF gene therapy in patients with congenital deafness. Longer follow-up and larger cohorts are needed to establish the safety and efficacy of repeated administration of gene therapies. Trial registration no.: ChiCTR2200063181 .

PMID:
42362868
Bibliographic data and abstract were imported from PubMed on 27 Jun 2026.

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