Gene therapy for inherited deafness is moving toward human trials, but researchers need better animal models to optimize treatments before testing them in children. The challenge lies in bridging the gap between promising mouse studies and clinical applications for one of the most common genetic causes of childhood hearing loss.
Scientists have successfully created marmoset monkeys with complete disruption of the OTOF gene, which codes for otoferlin, a protein essential for sound transmission in inner ear hair cells. Using CRISPR gene editing on fertilized eggs, they generated non-mosaic knockout animals that exhibit the same auditory synaptopathy seen in human OTOF mutations. The marmosets showed profound hearing impairment with intact cochlear structure but failed synaptic transmission, precisely mirroring the human condition where everything works normally until the final step of converting sound to neural signals.
This represents a significant methodological advance in translational hearing research. Most genetic hearing loss studies rely on rodent models, but primate inner ear anatomy and physiology more closely resemble humans, particularly in cochlear dimensions and auditory processing complexity. The OTOF gene therapy field has shown remarkable promise in mouse studies using adeno-associated virus vectors to restore hearing, leading to current pediatric clinical trials. However, questions about optimal dosing, delivery methods, and long-term safety require validation in models with greater translational relevance. The successful generation of non-mosaic knockouts also demonstrates technical progress in primate genetic engineering, avoiding the complications of partial gene disruption that can confound research outcomes. These marmoset models will likely accelerate the development of more effective gene therapies for the estimated 200,000 people worldwide with OTOF-related deafness.