Background: Neutralizing antibodies after the first dose and treatment of the opposite ear

Preliminary clinical findings published in Nature Medicine report improved auditory function after adeno-associated virus (AAV) gene therapy was administered again, this time to the opposite ear, in four children with congenital OTOF-related deafness. This single-arm trial enrolled patients who had developed neutralizing antibodies after their first dose and assessed whether the second ear could be treated in the presence of those antibodies.

Neutralizing antibodies induced by an initial dose can make repeat dosing of AAV gene therapy difficult. In an earlier single-arm trial, the researchers reported safety and hearing improvement after one dose of AAV-hOTOF in patients with OTOF-related deafness. The present study examined outcomes when a second dose was given to the opposite ear, rather than the ear treated first. It should therefore be distinguished from studies that use repeat dosing in the same ear to supplement the treatment effect.

Key findings: Improved auditory measures at week 26 and safety assessment

The researchers first administered a repeat dose of AAV1-hOTOF to the opposite ear of Otof-deficient mice when serum neutralizing antibody titers had peaked. In this preclinical experiment, they reported hearing recovery with limited immune activation.

The team then amended the protocol of an ongoing clinical trial and enrolled four patients aged 2.2–3.4 years who had previously received one dose of gene therapy. Their pre-existing neutralizing antibody titers ranged from 1:135 to 1:3,645. After a second dose was given to the opposite ear, they were followed for 26–52 weeks. The primary endpoint was the occurrence of dose-limiting toxicity within six weeks after dosing; secondary endpoints included safety and auditory function.

Before treatment, the mean auditory brainstem response (ABR) threshold in the second treated ear exceeded 95 dB in all patients. At week 26, it had decreased to 43 dB, 63 dB, 80 dB and 53 dB in patients 1–4, respectively. Auditory measures improved, but outcomes varied among patients. The provided abstract does not report results that would establish restoration of normal hearing or improvement in language ability.

No dose-limiting toxicity occurred within six weeks. In the safety assessment, adverse events were grade 1–2 except for one grade 3 decrease in neutrophil count; no serious adverse events were reported. This does not mean that no adverse events occurred. Based on the provided abstract alone, it is difficult to determine whether the decrease in neutrophil count was related to treatment.

Meaning and outlook: Preliminary evidence for sequential treatment of both ears

These findings show that auditory improvement may be observed after gene therapy in the opposite ear of patients with OTOF-related deafness who developed neutralizing antibodies after their first dose. However, because this was a single-arm trial with four patients, its ability to assess differences in effect versus a comparator group or predict outcomes in a broader patient population is limited.

The researchers stated that larger cohorts and long-term follow-up are needed to establish the safety and efficacy of repeat dosing. The durability of hearing improvement and long-term safety remain to be evaluated in subsequent studies. Whether the same results can be achieved with repeat dosing in the same ear or with AAV treatments for other diseases also requires separate investigation.

The study was summarized based on the provided bibliographic information and abstract for the Nature Medicine paper.