PAM-flexible adenine base editing rescues hearing loss in a humanized MPZL2 mouse model harboring an East Asian founder mutation

Abstract Hearing loss is one of the most prevalent sensory disorders, but no commercial biological treatments are currently available. Here, we identified an East Asia-specific founder mutation, the homozygous c.220C>T mutation in MPZL2 , that contributes to a significant proportion of hereditary deafness cases in our cohort study. We found that the disease-causing mutation could be targetable by adenine base editors (ABEs) that enable A·T-to-G·C base corrections without DNA double-strand breaks. To demonstrate this, we developed a humanized mouse model ( hMPZL2 Q74X/Q74X ) that recapitulates human MPZL2 deafness and leads to progressive hearing loss. A PAM-flexible ABE variant with reduced bystander and off-target effects (ABE8eWQ-SpRY:sgRNA3) was packaged in dual adeno-associated viruses (AAVs) and injected into the inner ear of hMPZL2 Q74X/Q74X mice and effectively corrected the mutation. This treatment significantly restored hearing function, improved inner ear structural integrity, and reversed altered gene expression. Base editing may hold therapeutic potential for hereditary deafness, including most cases of MPZL2 deafness.