Gene therapy trial: restored hearing in children with hereditary deafness

In a recent study published in Nature Medicine, researchers evaluated the safety and effectiveness of binaural adeno-associated virus 1 (AAV1)-human otoferlin (hOTOF) therapy in five children with autosomal recessive deafness 9 (DFNB9).

Study: Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Image Credit: GUNDAM_Ai/Shutterstock.comStudy: Bilateral gene therapy in children with autosomal recessive deafness 9: single-arm trial results. Image Credit: GUNDAM_Ai/


Millions of individuals worldwide suffer from hearing loss as a result of OTOF gene abnormalities, which cause DFNB9.

Gene therapy is a viable treatment option for hereditary deafness, with research indicating that unilateral AAV1-hOTOF gene therapy is safe and related to functional benefits.

Bilateral hearing restoration may provide additional benefits, such as improved speech perception and sound source localization. However, pre-existing neutralizing antibodies against AAV can prevent AAV vector-induced infection in target cells and tissues, resulting in immunotoxicity and limiting repeat delivery.

About the study

The present study investigated whether AAV1-hOTOF binaural gene therapy is safe and effective in DFNB9 patients.

The researchers assessed 316 volunteers for eligibility, of whom five pediatric individuals (three boys and two girls) had congenital hearing impairment in both ears resulting from biallelic OTOF gene mutations enrolled between July 14 and November 15, 2023.

Participants had OTOF gene mutations and auditory brainstem response (ABR) levels of ≥65 dB in both ears. Exclusion criteria included having a ratio of neutralizing antibodies to AAV1>1:2,000, preexisting otologic disease, a history of substance abuse, complex immunodeficiency or organ transplantation, a history of neurological or psychiatric disorders, and a history of radiotherapy and chemotherapy.

During the one-time surgery, the researchers injected 1.50 × 1012 vector genomes (vg) of AAV1-hOTOF into the patient's bilateral cochleae via the ear’s round window.

When compared to unilateral injection, bilateral injection increased operative time by twofold. They assessed the first three patients over 26 weeks and the remaining two for 13 weeks.

The primary outcome was dosage-limiting toxicity after six weeks, whereas the secondary endpoints were safety (adverse events) and effectiveness (auditory function and speech perception). The study investigated additional advantages of bilateral ear therapy for DFNB9 patients in loud environments and sound source localization.

Toxicity grade was determined using Common Terminology Criteria for Adverse Events, fifth version (CTCAE V5.0). Tests, including auditory steady-state responses (ASSR), ABR, and distortion product otoacoustic emission (DPOAE), assessed patients' auditory functioning, sound source localizing, and speech perceptions.

The researchers analyzed the Meaningful Auditory Integration Scale (MAIS) or IT-MAIS, Categories of Auditory Performance (CAP), and Meaningful Use of Speech Scale (MUSS) scores.

They evaluated speech perception using the Speech Intelligibility Rating (SIR) and sound origin localizing ability using the Spatial and Other Qualities of Hearing Scale for Parents (SSQ-P) scores.

The researchers administered dexamethasone intravenously for eight days, beginning three days before the AAV1-hOTOF bilateral injection to reduce inflammation. They studied ear structure using computed tomography (CT) and magnetic resonance imaging (MRI).

They analyzed Sanger sequencing findings and interpreted OTOF variants. They performed whole-exome sequencing to genotype the samples. They sampled blood from the participants to measure anti-AAV1 neutralizing antibody titers. Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) responses to AAV1 indicated circulating T-cell responses in blood.


The participants did not develop dosage-limiting toxicity reactions or serious adverse events. The researchers found 36 adverse occurrences, graded 1 or 2, the most prevalent being elevated lymphocyte counts (six of 36) and cholesterol levels (six of 36).

They noticed regular ear anatomy post-injection. All patients received bilateral hearing restorations. At baseline, the mean ABR cutoff for the right (left) ear exceeded 95 decibels.

At 26 weeks, the cutoff restored to 58 decibels (58 decibels) in the first patient, 75 decibels (85 decibels) in the second patient, 55 decibels (50 decibels) in the third patient, 75 decibels (78 decibels) in the fourth patient, and 63 decibels (63 decibels) in the fifth patient.

After 13 weeks of treatment, the mean ABR thresholds in five patients receiving binaural treatment were 69 dB. In five patients receiving unilateral treatment, they exceeded 64 decibels. The average ASSR thresholds were 60 dB for bilateral gene therapy patients and 67 decibels for unilateral patients treated with 1.50 × 1012 vg AAV1-hOTOF.

All five patients had their speech perception and ability to localize sound sources restored. The team found that the MAIS, IT-MAIS, CAP, or MUSS scores improved in all patients.

Six weeks after treatment, all patients developed AAV1-neutralizing antibodies.  Neutralizing antibody titers among bilateral gene therapy recipients were 1:1,215, and among those receiving a unilateral dose, the titers ranged from 1:135-1:3,645.

Findings indicated that the bilateral injection group possessed more neutralizing antibodies. A week following treatment, no patient's blood tested positive for vector deoxyribonucleic acid (DNA).  Six weeks following AAV1-hOTOF binaural gene therapy, IFN-γ ELISpot responses to AAV1 capsid peptide pools were negative.


Based on the study findings, AAV1-hOTOF binaural gene therapy is feasible, safe, and effective for DFNB9 patients. Study results broaden the treatment options and encourage gene therapy for hereditary deafness caused by different genes.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.


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