Targeting the cause, not the symptom: The new paradigm in pediatric hearing care
Industry Buzz
As a physician, it's humbling to see the impact of advances in genetic testing and how many genes specifically known to cause sensorineural hearing loss, SNHL, can be tested at a single point of testing.
—Julie Wei, MD, director of otolaryngology at Akron Children's Hospital
Pediatric hearing care is shifting from “optimize audibility” to “treat the lesion.” For decades, the center of gravity was devices: hearing aids, bone conduction systems, cochlear implants. Those tools still matter. But for certain genetic subtypes, the goal now looks different: restore physiologic hearing by correcting the defective mechanism.[][]
Julie Wei, MD, director of otolaryngology at Akron Children's Hospital, says, “As a physician, it's humbling to see the impact of advances in genetic testing and how many genes specifically known to cause sensorineural hearing loss, SNHL, can be tested at a single point of testing. Once SNHL is confirmed, depending on if it's unilateral or bilateral, other identifiable medical issues are assessed or ruled out. I offer genetic testing to patients when there is strong family history and/or simply as an option for parents to have an answer.”
OTOF-related hearing loss is one of the clearest test cases for this shift.[]
OTOF encodes otoferlin, a key protein for synaptic vesicle release at inner hair-cell ribbon synapses. In DFNB9, a type of OTOF-related hearing loss, hair cells can be structurally present, but synaptic transmission fails. Clinically, this can look like congenital severe-to-profound loss, often with an auditory neuropathy phenotype.
Historically, cochlear implants have been the main option. They bypass the damaged synapse and stimulate the auditory nerve directly. Outcomes can be good, but physiology is not restored. Families still face lifelong device dependence.[]
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Now the target is the gene itself.[] Two major clinical programs have pushed the field forward with dual adeno-associated viral (AAV) strategies designed to deliver the full-length OTOF coding sequence, which is too large for a standard single AAV payload.
Akouos (subsidiary of Eli Lilly) reported early clinical results from AK-OTOF-101, noting hearing restoration in the first participant within 30 days after a one-time intracochlear administration.[]
Regeneron’s DB-OTO program has reported functional gains in children treated in the CHORD study, including speech perception improvements. Updated reports describe clinically meaningful hearing improvements in most participants and plans for regulatory discussions.[][]
How it works
DB-OTO is a hair-cell-specific dual-vector AAV-based therapy designed to restore hearing in OTOF-related loss. It uses two AAV1 vectors reconstituting functional OTOF.[] The scientific backbone of the approach is straightforward:
Two AAV vectors deliver split-gene payloads.
In the target cell, a full-expression cassette is reconstituted.
Otoferlin expression is restored in inner hair cells.
Synaptic transmission improves.
Auditory pathway input becomes acoustic again, not device-mediated.
Timely intervention is key
For clinicians, a logical workflow toward gene therapy should include:
Genotype earlier: If OTOF is on the differential, genetic confirmation becomes time-sensitive. Missing the diagnosis does not only delay counseling. It can also delay eligibility for trials and emerging therapies.
Reframe implant conversations: Cochlear implantation remains standard. But for DFNB9, some families will ask about biology-based options before committing to an irreversible pathway. The counseling needs to be accurate, neither sales-y nor dismissive.
Explain endpoints families understand: Parents care about their child’s spoken language, classroom function, localization, and listening effort. They do not care about “threshold shifts” alone.
Plan for long follow-up: Even if early auditory responses appear fast, long-term durability is the real question. Families need a plan for ongoing audiology testing, speech-language support, and outcome tracking over years.
Lawrence Lustig, MD, investigator for the CHORD study, described the broader implications of a viable genetic treatment pathway.[] “This is going to be big for the field,” he said in an interview. ”Now that we have a treatment for genetic deafness, our hope is that this will spur universal genetic testing in all kids with hearing loss.…”
What makes OTOF-related hearing loss different from many other congenital hearing loss etiologies is the match between biology and delivery. The target cells are accessible surgically, the mechanism is monogenic, and the therapeutic goal is measurable through both objective responses and real-world speech perception.
Related: The evolution of dual-AAV strategies for congential hearing loss: From concept to clinical potential