AAV Gene Therapy Restores Hearing in OTOF Mutation Patients, Study in Nature Medicine Reports

Gene Therapy Offers Hearing Restoration for OTOF Mutation Patients

A novel gene therapy has demonstrated the ability to reverse congenital deafness and severe hearing impairment in children and adults. Scientists at Karolinska Institutet, alongside Chinese medical institutions and universities, conducted a clinical trial involving ten patients aged 1 to 24 with OTOF gene mutations, a rare cause of congenital hearing loss. The treatment utilized a synthetic adeno-associated virus (AAV) to deliver a functional OTOF gene directly into the inner ear through a single injection. Most participants experienced partial hearing restoration within a month, with average sound detection thresholds improving from 106 decibels to 52 after six months. Children aged 5–8 exhibited the most significant improvements, including a seven-year-old girl who achieved near-complete hearing recovery within four months. The therapy was generally well-tolerated, with the most common adverse effect being a temporary reduction in neutrophil counts. Researchers highlighted that OTOF is the first target in a broader initiative to develop therapies for other genetic causes of deafness, such as GJB2 and TMC1 mutations. The study, published in Nature Medicine, received funding from Chinese research initiatives and Otovia Therapeutics Inc.

“the next step is to treat patients with other gene mutations, such as GJB2”

Mechanism of AAV-Based Gene Therapy

The OTOF gene produces otoferlin, a calcium-binding protein critical for converting sound signals into neural signals. Otoferlin enables inner hair cells to release neurotransmitters to the auditory nerve, facilitating the transformation of sound waves into electrical impulses interpreted by the brain. Adeno-associated virus (AAV) vectors function as modified viral carriers that safely deliver functional OTOF genes into cochlear cells. The treatment involves a minimally invasive procedure where an endoscope lifts the eardrum to access the round window, a small opening leading to the cochlea. A specialized probe then administers a single, small dose of the functional OTOF gene directly into the inner ear. The AAV used in the trial, Anc80L65, is a capsid variant optimized for cochlear transduction. Once inside the cochlear cells, the gene allows sensory cells to produce functional otoferlin, restoring their ability to respond to sound and activate the auditory nerve. This in vivo gene therapy approach demonstrated promising results, with 16 of 17 children showing hearing recovery, improving from profound levels (>95 dB) to mild-moderate levels (30–58 dB). OTOF mutations account for 1–8% of congenital nonsyndromic hearing loss, making this therapy significant for treating autosomal recessive auditory neuropathy spectrum disorder (ANSD).

“Hearing loss is the most common sensory defect, affecting 2 per 1,000 newborns”