Gene therapy trial: restoring hearing in children with hereditary deafness

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

Millions of people around the world suffer from hearing loss caused by abnormalities of the OTOF gene, leading to the development of DFNB9.

Gene therapy is a promising treatment option for hereditary deafness, and studies show that unilateral AAV1-hOTOF therapy is safe and associated with functional benefits.

Binaural hearing restoration may provide additional benefits such as improved speech perception and sound source localization. However, existing neutralizing antibodies against AAV can prevent infection of target cells and tissues by causing immunotoxicity and limiting re-delivery.

The present study aimed to evaluate the safety and efficacy of binaural AAV1-hOTOF gene therapy in patients with DFNB9.

Researchers assessed 316 volunteers for the study, of whom five children (three boys and two girls) with congenital hearing loss in both ears due to biallelic mutations of the OTOF gene were enrolled in the study between July 14 and November 15, 2023.

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

In a one-time operation, researchers injected 1.50 x 10^12 AAV1-hOTOF vector genomes (vg) into patients' bilateral cochleae through the round window of the ear.

Participants experienced no dose-limiting toxicities or serious adverse events. There were 36 grade 1 or 2 adverse events, the most common being elevated lymphocyte levels (six of 36) and cholesterol (six of 36).

All patients received bilateral hearing restoration. At the beginning of the study, the average ABR threshold for the right (left) ear exceeded 95 dB.

After 26 weeks, the threshold had recovered to 58 dB (58 dB) in the first patient, 75 dB (85 dB) in the second patient, 55 dB (50 dB) in the third patient, 75 dB (78 dB) in the fourth patient and 63 dB (63 dB) in the fifth patient.

Thirteen weeks after treatment, the average ABR thresholds of the five patients receiving binaural treatment were 69 dB. In five patients receiving unilateral treatment, they exceeded 64 dB. Average ASSR thresholds were 60 dB for patients receiving binaural gene therapy and 67 dB for patients receiving unilateral treatment.

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

Six weeks after treatment, all patients had developed neutralizing antibodies to AAV1. Neutralizing antibody titers in binaural gene therapy recipients were 1:1,215, while titers in unilateral dose recipients ranged from 1:135 to 1:3,645.

A week after treatment, not a single patient’s blood showed a positive result for vector DNA. Six weeks after binaural AAV1-hOTOF gene therapy, IFN-γ ELISpot responses to AAV1 capsid peptide pools were negative.

Based on the study results, binaural AAV1-hOTOF gene therapy is safe and effective for patients with DFNB9. The study results expand treatment options and stimulate further development of gene therapy for hereditary deafness caused by various genes.