GJB2 gene therapy and conditional deletion reveal developmental stage-dependent effects on inner ear structure and...

Area of Science:

• Genetics
• Otolaryngology
• Molecular Biology

Background:

• Pathogenic variants in the GJB2 gene, encoding connexin 26, are the leading cause of autosomal-recessive hereditary deafness.
• Current understanding of pathogenic mechanisms for GJB2-related deafness is limited, and effective cures are unavailable.
• Existing mouse models with Gjb2 loss in cochlear supporting cells rapidly develop profound deafness, hindering therapeutic development.

Purpose of the Study:

• To create a novel inducible mouse model for studying GJB2-related deafness.
• To investigate the cochlear biology of connexin 26.
• To evaluate potential therapeutic strategies for GJB2-related hearing loss.

Main Methods:

• Generated inducible Sox10iCre;Gjb2 conditional knockout mice.
• Administered tamoxifen to induce Gjb2 loss.
• Assessed cochlear phenotype, including hair cell and neuron survival, for two months post-induction.
• Attempted AAV-mediated GJB2 gene transfer in mature mutant ears.

Main Results:

• Inducible Gjb2 loss in mice resulted in reduced connexin 26 expression and impaired cochlear function.
• Hair cells and neurons survived for two months, enabling therapeutic intervention studies.
• AAV-mediated GJB2 gene transfer did not improve hearing thresholds and, in some cases, worsened hearing loss and caused hair cell loss.
• The Sox10iCre;Gjb2 mice provide a valuable model for studying connexin 26 in the cochlea.

Conclusions:

• The Sox10iCre;Gjb2 mouse model is suitable for studying connexin 26 biology in the cochlea.
• This model can be utilized for evaluating gene therapy vectors and developing therapies for GJB2-related deafness.
• Further research is needed to understand the limitations of gene therapy in this model and to develop effective treatments for hereditary deafness.