Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results

Abstract

Gene therapy is a promising approach for hereditary deafness. We recently showed that unilateral AAV1-hOTOF gene therapy with dual adeno-associated virus (AAV) serotype 1 carrying human OTOF transgene is safe and associated with functional improvements in patients with autosomal recessive deafness 9 (DFNB9). The protocol was subsequently amended and approved to allow bilateral gene therapy administration. Here we report an interim analysis of the single-arm trial investigating the safety and efficacy of binaural therapy in five pediatric patients with DFNB9. The primary endpoint was dose-limiting toxicity at 6 weeks, and the secondary endpoint included safety (adverse events) and efficacy (auditory function and speech perception). No dose-limiting toxicity or serious adverse event occurred. A total of 36 adverse events occurred. The most common adverse events were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36). All patients had bilateral hearing restoration. The average auditory brainstem response threshold in the right (left) ear was >95 dB (>95 dB) in all patients at baseline, and the average auditory brainstem response threshold in the right (left) ear was restored to 58 dB (58 dB) in patient 1, 75 dB (85 dB) in patient 2, 55 dB (50 dB) in patient 3 at 26 weeks, and 75 dB (78 dB) in patient 4 and 63 dB (63 dB) in patient 5 at 13 weeks. The speech perception and the capability of sound source localization were restored in all five patients. These results provide preliminary insights on the safety and efficacy of binaural AAV gene therapy for hereditary deafness. The trial is ongoing with longer follow-up to confirm the safety and efficacy findings. Chinese Clinical Trial Registry registration: ChiCTR2200063181 .

Fig. 1. Patient enrollment.

Five patients were enrolled to receive binaural gene therapy and were evaluated for the primary endpoint. CI, cochlear implant. Source data

Fig. 2. Audiometric test.

a–e, The ABR and ASSR thresholds of patients 1 (a), 2 (b), 3 (c), 4 (d) and 5 (e). The arrows indicate no response even at the maximum sound intensity level. Arrows pointing left and downward, right ear; arrows pointing right and downward, left ear.

Extended Data Fig. 1. Sanger sequencing results in patients and family members.

Mutation 1 indicates the mutation in OTOF allele 1. Mutation 2 indicates the mutation in OTOF allele 2. Proband indicates the patient. Het, heterozygous; WT, wildtype. The sanger sequencing results in parents of patients 1, 3, 4, and 5 are provided. The sanger sequencing result in father of patient 2 is provided. The sanger sequencing result in grandfather of patient 2 is provided, because the mother of patient 2 passed away.

Extended Data Fig. 2. The signal-to-noise ratio of the DPOAE in patients at baseline and follow-up visits.

a–c, In patients 1, 2 and 3, the SNR of DPOAE decreased at most of frequencies at 4 weeks and showed the tendency to recover to the baseline at following timepoints. d, The SNR of DPOAE in both ears of patient 4 was stable at some frequencies at 4 weeks and 6 weeks, but it decreased at most frequencies at 13 weeks. e, The SNR of DPOAE in patient 5 was stable at some frequencies at 4 weeks, but it decreased at some frequencies at 6 weeks and showed recovery to some extent at 13 weeks. SNR: signal-to-noise ratio. DPOAE: distortion product otoacoustic emission.

Extended Data Fig. 3. Computed tomography in patients’ ears.

The images from computed tomography showed that no abnormal structure was observed in both ears of patients 1 (a), 2 (b), 3 (c), 4 (d) or 5 (e) at baseline and 6 weeks after gene therapy.

Extended Data Fig. 4. Magnetic resonance imaging in patients’ ears.

a–e. The images from magnetic resonance imaging showed that no abnormal structure was observed in patients’ ears at baseline and 6 weeks after gene therapy.

Extended Data Fig. 5. Interferon-gamma ELISpot responses to the AAV1 capsid peptide pools in patients.

Interferon-gamma was detected by ELISpot assay in patients 1 (a), 2 (b), 3 (c), 4 (d), and 5 (e). T cell responses to the AAV1 capsid were negative in 5 patients at baseline and 6 weeks after AAV1-hOTOF gene therapy. SFU, spot-forming unit. NC: negative control; PC: positive control.