MDLinxThe Evolution of Dual-AAV Strategies for Congenital Hearing Loss: From Concept to Clinical Potential

Dual adeno-associated virus gene therapy restored normal hearing in 3 of 12 children with OTOF-related deafness in the 2025 CHORD trial. This single-administration, intracochlear therapy represents the first human proof point for large-gene delivery in congenital hearing loss.

⚕️ Clinical Considerations

• OTOF-related deafness, a synaptic transmission disorder, is now a viable gene therapy target, with dual-AAV splitting the oversized payload across two vectors for full-length protein reconstitution
• No drug-related adverse events were reported in 12 pediatric participants; transient vestibular effects in 5 patients resolved within 6 days
• Genetic testing remains inconsistently adopted due to cost, emotional barriers, and parental perception of limited clinical utility, creating a referral gap as therapies advance
• Long-term durability, bilateral dosing outcomes, and functional communication gains beyond hearing thresholds remain unproven

🎯 Practice Applications

• Refer all children with severe-to-profound hearing loss for genetic testing to identify OTOF candidacy
• Counsel families that genetic results will increasingly influence treatment options, not just monitoring schedules
• Discuss transient vestibular risks when introducing gene therapy as an emerging option
• Monitor CHORD trial follow-up data for multi-year durability evidence before routine referral

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