Patients

We screened 316 participants for eligibility (Fig. 1). Five pediatric patients (two girls and three boys) with bilateral congenital hearing loss caused by biallelic OTOF mutations were enrolled from 14 July 2023 to 15 November 2023 (Fig. 1 and Table 1). Details of Sanger sequencing results and OTOF variant interpretation in patients are provided in Extended Data Fig. 1 and Extended Data Table 1. The average auditory brainstem response (ABR) threshold was >95dB in all patients at baseline (Table 1). None of the patients received cochlear implants before the trial. A dose of 1.51012vector genomes (vg) AAV1-hOTOF per ear, selected on the basis of the previous unilateral study11, was subsequently injected into the bilateral cochleae of the patient through the round window during a one-time operation. We have completed a 26-week assessment in patients 1, 2 and 3, and a 13-week assessment in patients 4 and 5. The study is ongoing.

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

Source data

The primary endpoint was dose-limiting toxicity, defined as hematologic toxicity grade 4, nonhematologic toxicity grade 3 or aural toxicity grade 2 within 6weeks. The grade was assessed according to Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE V5.0). The dose of 1.51012vg AAV1-hOTOF was selected for bilateral treatment based on the results of the unilateral study that tested different doses11. No dose-limiting toxicity happened in five patients receiving binaural gene therapy with a dose of 1.51012vg AAV1-hOTOF per ear.

Efficacy outcomes include auditory function and speech perception. ABR, auditory steady-state response (ASSR), distortion product otoacoustic emission (DPOAE), and related questionnaires and tests were used to evaluate the auditory function, speech perception and sound source localization in patients.

At baseline, the average ABR threshold in the right (left) ear was >95dB (>95dB) in all five patients. In patient 1, the average ABR threshold in the right (left) ear was restored to 65dB (68dB) at 4weeks, 63dB (63dB) at 6weeks, 63dB (63dB) at 13weeks and 58dB (58dB) at 26weeks; the average ASSR threshold in the right (left) ear was 103dB (103dB) at baseline, and was restored to 48dB (63dB) at 4weeks, 53dB (58dB) at 6weeks, 53dB (58dB) at 13weeks and 53dB (58dB) at 26weeks (Fig. 2a). In patient 2, the average ABR threshold in the right (left) ear was >95dB (>95dB) at 4weeks, >85dB (>95dB) at 6weeks, 83dB (88dB) at 13weeks and 75dB (85dB) at 26weeks; the average ASSR threshold in the right (left) ear was 88dB (83dB) at 4weeks, 73dB (85dB) at 6weeks, 61dB (64dB) at 13weeks and 60dB (60dB) at 26weeks, compared with 79dB (81dB) at baseline (Fig. 2b). In patient 3, the average ABR threshold in the right (left) ear was restored to 63dB (63dB) at 4weeks, 63dB (60dB) at 6weeks, 60dB (58dB) at 13weeks and 55dB (50dB) at 26weeks; the average ASSR threshold in the right (left) ear was restored to 58dB (63dB) at 4weeks, 60dB (65dB) at 6weeks, 63dB (60dB) at 13weeks and 53dB (53dB) at 26weeks, compared with 100dB (100dB) at baseline (Fig. 2c). In patient 4, the average ABR threshold in the right (left) ear was >95dB (>95dB) at 4weeks, >90dB (>95dB) at 6weeks and 75dB (78dB) at 13weeks; the average ASSR threshold in the right (left) ear was restored to 95dB (95dB) at 4weeks, 85dB (85dB) at 6weeks and 63dB (60dB) at 13weeks, compared with 106dB (106dB) at baseline (Fig. 2d). In patient 5, the average ABR threshold in the right (left) ear was restored to 68dB (75dB) at 4weeks, 70dB (68dB) at 6weeks and 63dB (63dB) at 13weeks; the average ASSR threshold in the right (left) ear was restored to 68dB (71dB) at 4weeks, 60dB (65dB) at 6weeks and 60dB (63dB) at 13weeks, compared with 85dB (88dB) at baseline (Fig. 2e).

ae, 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.

In both ears of patients 13, the signal-to-noise ratio (SNR) of DPOAE decreased at most frequencies at 4weeks and gradually recovered at the later follow-up (Extended Data Fig. 2ac). In patient 4, the SNR was stable at some frequencies at 4weeks, decreased to some extent at later follow-up and has not recovered at 13weeks (Extended Data Fig. 2d). In patient 5, the SNR decreased at some frequencies at 6weeks and recovered to some degree at 13weeks (Extended Data Fig. 2e).

In patient 1, the Meaningful Auditory Integration Scale (MAIS) and Categories of Auditory Performance (CAP) scores were 1 and 0, respectively, at baseline, and 28 and 4, respectively, at 26 weeks; the Speech Intelligibility Rating (SIR) and Meaningful Use of Speech Scale (MUSS) scores were 1 and 0, respectively, at baseline, and 1 and 7, respectively, at 26 weeks. The Speech of the Speech, Spatial, and Other Qualities of Hearing Scale for Parents (SSQ-P), the Spatial of the SSQ-P and the Other Qualities of the SSQ-P scores were 0.3, 0 and 0, respectively, at baseline, and were improved to 7.8, 2.8 and 5.0, respectively, at 26weeks (Table 2). In a quiet environment, the perception of monosyllable, disyllable and sentence was all 0% at baseline and 2.0%, 1.4% and 0%, respectively, at 26weeks after treatment; ambient sound, tone, initial and final was all 0% at baseline, and 31.3%, 31.3%, 20.8% and 20.8%, respectively, at 26weeks (Extended Data Table 2). For sound source localization tests, the bilateral root mean square error (RMSE) was 92.81.1 at baseline and 40.01.7 at 26weeks; when one ear was covered, the unilateral RMSE (75.51.0) at 26weeks was worse (Extended Data Table 2). In Supplementary Video 1, patient 1 could not hear at baseline and could recognize sound 4weeks and 6weeks after injection. At 13weeks, she could speak syllables such as a, ba (father), i, u, s and ma (mother). She was able to complete the sound localization test well at 13weeks.

In patient 2, the InfantToddler MAIS (IT-MAIS) and CAP scores were 0 and 0, respectively, at baseline, and 35 and 5, respectively, at 26 weeks; the SIR and MUSS scores were 1 and 0, respectively, at baseline, and 2 and 9, respectively, at 26 weeks; the Speech of the SSQ-P, the Spatial of the SSQ-P and the Other Qualities of the SSQ-P scores were all 0 at baseline and 6.7, 5.3 and 8.5, respectively, at 26weeks (Table 2). In Supplementary Video 2, patient 2 could not respond to sound and music at baseline, but he was able to turn to the sound source when his name was called from the left and right of his backward side 6weeks after injection. He could dance to the music and complete some simple instructions at 15weeks, and he could say some simple words, for example, ayi (aunt) and bai (bye), and communicate with others at 26weeks.

In patient 3, the IT-MAIS or MAIS, and CAP, scores were all 0 at baseline, and 35 and 5, respectively, at 26weeks; the SIR and MUSS scores were 1 and 0, respectively, at baseline, and 2 and 15, respectively, at 26weeks; the Speech of the SSQ-P, the Spatial of the SSQ-P and the Other Qualities of the SSQ-P scores were all 0 at baseline, and 7.3, 8.0 and 8.5, respectively, at 26 weeks (Table 2). In Supplementary Video 3, patient 3 had no response to sound and music at baseline, but he could turn back when his name was called 3weeks after injection. At 13weeks, he was able to move his body and dance when he heard the music. He was able to say some simple words at 26weeks, such as baba (father), nainai (grandmother) and yeye (grandfather).

In patient 4, the MAIS and CAP scores were 2 and 0, respectively, at baseline, and 16 and 4, respectively, at 13weeks; the SIR and MUSS scores were 1 and 2, respectively, at baseline, and 1 and 7, respectively, at 13weeks; the Speech of the SSQ-P, the Spatial of the SSQ-P and the Other Qualities of the SSQ-P scores were 0.3, 0 and 0, respectively, at baseline, and 3.6, 5.8 and 4.5, respectively, at 13weeks (Table 2). In Supplementary Video 4, patient 4 had no response to sound at baseline, but she could turn back when her name was called 4weeks after injection. She could complete some instructions at 13weeks, and she could say simple words at 20weeks, for example, baba (father), mama (mother) and nainai (grandmother).

In patient 5, the IT-MAIS or MAIS, and CAP, scores were 2 and 0, respectively, at baseline, and 29 and 4, respectively, at 13weeks; the SIR and MUSS scores were 1 and 0, respectively, at baseline, and 2 and 7, respectively, at 13weeks; the Speech of the SSQ-P, the Spatial of the SSQ-P and the Other Qualities of the SSQ-P scores were 0.2, 0 and 0, respectively, at baseline, and 7.6, 7.2 and 6.6, respectively, at 13weeks (Table 2).

To minimize the potential inflammatory response, dexamethasone was used intravenously for 8days starting from 3days before AAV1-hOTOF bilateral injection. No serious adverse event (AE) occurred. A total of 36 AEs occurred (Table 3), including emesis (patient 1), fever (patient 2), increased lymphocyte counts (patients 14), decreased lymphocyte counts (patient 3), decreased neutrophil counts (patient 2), decreased hemoglobin levels (patients 2 and 3), increased triglyceride levels (patient 2), increased cholesterol levels (patients 25), transient reduction in fibrinogen levels (patient 3), increased creatine phosphokinase levels (patient 2), decreased haptoglobin levels (patients 1 and 5), increased lactate dehydrogenase levels (patients 25), hyperglycemia (patient 5), proteinuria (patient 1) and hematuresis (patients 1 and 4). All 36 AEs were grade 1 or 2. The most common AEs were increased lymphocyte counts (6 out of 36) and increased cholesterol levels (6 out of 36), followed by increased lactate dehydrogenase levels (5 out of 36). In patient 1, emesis occurred at 2h after injection and was resolved with symptomatic treatment within 1day. In patient 2, fever (highest temperature, 38.7C) occurred at 18days and 29days after injection, with mild cough and increased lymphocyte counts, but no evidence of pneumonia or other concomitant symptoms.

In addition, the structure of the ears was observed by computed tomography and magnetic resonance imaging, showing the normality of the ear structure after injection (Extended Data Figs. 3 and 4).

Neutralizing antibodies against AAV1 were increased in all patients at 6weeks after treatment (Extended Data Table 3). Vector DNA in the blood was not detectable in any patient at 7days after treatment (Extended Data Table 3). Interferon gamma (IFN-) enzyme-linked immunosorbent spot (ELISpot) responses to AAV1 capsid peptide pools with peripheral blood mononuclear cells (PBMCs) drawn from each patient at 6weeks after AAV1-hOTOF binaural gene therapy were negative (Extended Data Fig. 5)

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

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