Postnatal Slc26a4 gene therapy improves hearing and structural integrity in a hereditary hearing loss model

Area of Science:

• Genetics
• Otolaryngology
• Molecular Therapy

Background:

• Mutations in SLC26A4 cause DFNB4, a common hereditary hearing loss in Asia.
• Postnatal gene therapy for DFNB4 is unexplored due to model and intervention challenges.

Purpose of the Study:

• To investigate the preclinical efficacy of postnatal gene therapy for DFNB4 using a relevant mouse model.
• To identify a therapeutic window for intervention targeting cochlear structures.

Main Methods:

• Utilized a clinically relevant Slc26a4 mutant mouse model.
• Employed the synthetic AAV.Anc80L65 vector for SLC26A4 gene delivery to cochlear regions.
• Conducted comprehensive auditory and structural analyses.

Main Results:

• Achieved robust SLC26A4 delivery to the endolymphatic sac and cochlear lateral wall.
• Demonstrated significant hearing improvement and hair cell preservation in neonatal/juvenile treated mice.
• Observed sustained therapeutic effects into adulthood, including reduced degeneration and restored endocochlear potential.

Conclusions:

• Established a critical therapeutic window for DFNB4 postnatal gene therapy (neonatal to juvenile stages).
• Validated the feasibility of targeting the endolymphatic sac and cochlear lateral wall for DFNB4 intervention.
• Showcased the potential of AAV.Anc80L65-mediated gene therapy for treating hereditary hearing loss.