EMBO molecular medicineMay 20, 2026

Long-term recovery of hearing in a mouse model of inherited deafness using targeted DNA editing

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

Precise adenine base editing durably improved hearing-related outcomes in a KCNQ4 DFNA2 mouse model.

Evidence

A knock-in mouse model with human KCNQ4 c.961 G > A received dual-AAV ABE8e, achieving 21.4-28.9% organ-of-Corti correction and auditory benefit lasting at least 32 weeks at optimized lower doses.

Caveat

The results are preclinical and dose-sensitive, with toxicity a concern for dose optimization and only partial restoration of some cochlear functions.

Simplified

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.