Long-term restoration of auditory function in a DFNA2 mouse model by adenine base editing.

Hereditary hearing loss, the most prevalent genetic sensory disorder, lacks approved pharmacological therapies and represents a compelling target for gene correction. Pathogenic variants in KCNQ4 account for ~9.5% of autosomal dominant nonsyndromic cases. Prior gene-editing strategies disrupting mutant alleles have failed to achieve durable auditory rescue. Here we employed a knock-in mouse model harboring the human KCNQ4 c.961 G > A (p.G321S) mutation to evaluate precise base editing. Dual-AAV delivery of the adenine base editor ABE8e achieved 21.4-28.9% correction in the organ of Corti-the highest efficiency reported for genetic hearing loss. A dose-dependent therapeutic window emerged: higher doses promoted rapid recovery, whereas optimized lower doses minimized long-term toxicity and sustained functional benefit for at least 32 weeks. Treatment reduced auditory brainstem response thresholds by up to 49.09 dB SPL at optimal frequencies, mitigated degeneration of hair cells, spiral ganglion neurons, and auditory nerve fibers, and partially restored outer hair cell electrophysiology. These findings demonstrate the durability of precise mutation correction over allele-disruptive approaches and support clinical translation for KCNQ4-associated hearing loss.