Cell-specific delivery of GJB2 restores auditory function in mouse models of DFNB1 deafness and mediates appropriate expression in NHP cochlea.

ABSTRACT: Mutations in the GJB2 gene cause DFNB1, the most common hereditary hearing loss. GJB2 is expressed by cochlear epithelial cells and fibrocytes, but not by sensory hair cells or neurons. Attempts to treat DFNB1 mouse models with gene therapy have not substantially restored function, as inappropriate expression in hair cells and neurons might compromise their electrical activity. Here, we use ATAC-seq to identify candidate gene regulatory elements (GREs) that can drive cell-type-specific expression of GJB2. HA-tagged GJB2, delivered to a conditional knockout mouse with AAV vectors carrying GREs, is expressed by the appropriate cells, prevents degeneration, and rescues hearing by only 10-20 dB. In a Gjb2 partial knockdown model, a vector lacking HA prevents degeneration and completely restore

SUBMITTER: Ivanchenko MV 

PROVIDER: S-EPMC12708874 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature