Nicholas Grebe

A monumental moment in medical history: the first gene therapy for genetic hearing loss is now FDA approved. As a former Regeneron scientist, I feel very proud. I had the opportunity to hear about this programme while it was still in development. It’s one of the few programmes that, every time you came across it, you felt the medical breakthrough in your bones and privileged just to be there while it was happening. At this moment, it’s important that we look 30 years back when researchers mapped a locus on chromosome 2 to congenital deafness in a Lebanese family (pubmed.ncbi.nlm.nih.gov/8789…). They named it DFNB6 (later DFNB9) with no clue about the responsible gene. Three years later, the causal gene came to light: OTOF, encoding a protein called otoferlin (nature.com/articles/ng0499_3…). Seven years after that, in 2006, pioneering work by Christine Petit revealed that otoferlin is a calcium sensor in the inner hair cell membrane, acting as a molecular trigger that converts sound into electric signals that the brain can read (pubmed.ncbi.nlm.nih.gov/1705…). Twenty years fast forward, we now have a successful treatment. Thirty years from discovery to medicine. OTOF-related deafness is congenital, caused by complete deficiency of otoferlin. In these children, the cochlea is structurally intact, hair cells are there, the mechanics of sound transmission work. It’s just that final step, where hair cells hand off the signal to the auditory nerve through neurotransmitter release, that doesn’t happen. Sound arrives and dies at the synapse. It’s deafness due to a defect in the synapse caused by the absence of a single protein, which is what made this a beautiful, clean target for gene therapy. The treatment itself is a feat of molecular engineering. OTOF is too large to fit in a single AAV capsid. The team solved this elegantly by delivering the gene in two halves separately, which then get spliced to produce the full functional protein. A single surgical injection into the cochlea, a molecular miracle unfolds. Results from the CHORD trial were striking: of 20 evaluable patients, including children as young as 10 months, 80% showed meaningful hearing improvement, and by 48 weeks, 42% had achieved normal hearing including the ability to hear whispers. Otarmeni is not only the first gene therapy for deafness, it’s also the first dual-AAV therapy to be approved by the FDA. There are very few things in medicine that come close to giving back a sense like vision, hearing, or touch that a human never had from birth. It’s almost God’s work. A parent witnessing their child who was born deaf hearing their voice for the first time, it’s a joy that no words can describe. Multiply that by the fact that it came from a single injection, a repaired gene, and 30 years of science. We are truly in the golden era of medicine. Regeneron press release: investor.regeneron.com/news-… Below video is from the NEJM publication of CHORD trial (Valayannopoulos et al. NEJM 2025) nejm.org/doi/full/10.1056/NE…