What they found
TL;DR (qwen3.6:35b): This study demonstrates that re-administering AAV-mediated gene therapy to the contralateral ear is safe and effective in four pediatric patients who already had neutralizing antibodies against the virus. The treatment successfully improved hearing thresholds without causing serious adverse events, suggesting that pre-existing immunity does not necessarily prevent successful second-dose delivery.
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 .
How this applies to our program
While this paper focuses on OTOF rather than STRC/DFNB16, it provides critical proof-of-concept for overcoming immune barriers in gene therapy. This is directly relevant to the STRC program because STRC mutations often require large viral vectors or high expression levels, making the ability to re-administer therapy or bypass neutralizing antibodies essential for long-term clinical viability.
Key numbers
- 4 patients aged 2.2-3.4 years received a second dose
- Hearing thresholds improved from >95 dB to an average of 59.75 dB across the cohort
- Follow-up period ranged from 26 weeks to 52 weeks
Links
- pubmed_id: https://pubmed.ncbi.nlm.nih.gov/42362868/
- DOI: https://doi.org/10.1038/s41591-026-04505-4
Connections
[source]auto-indexed 2026-06-28 by strc-lit-watch