Exploring Embryonic and Postnatal Gene Therapy Approaches for GJB2-Related Deafness: A Scoping Review

Area of Science:

• Genetics and Molecular Biology
• Otolaryngology
• Regenerative Medicine

Background:

• Hearing loss (HL) significantly impacts quality of life, with genetic factors, particularly GJB2 gene mutations, causing many congenital cases.
• GJB2 mutations affect cochlear development and ion homeostasis, leading to hearing impairment.

Purpose of the Study:

• To review current knowledge on gene therapy for GJB2-related HL.
• To assess the feasibility and challenges of embryonic and postnatal gene therapy interventions.
• To identify key barriers to clinical translation.

Main Methods:

• A comprehensive scoping review of studies up to October 2025.
• Data extraction on GJB2 variants, animal models, gene delivery, outcomes, and ethics.
• Analysis of embryonic versus postnatal intervention strategies.

Main Results:

• Over 467 GJB2 variants identified; animal models show limited recovery with delayed gene therapy but better efficacy with early postnatal intervention.
• Adeno-associated virus (AAV) vectors achieved partial restoration of connexin expression and cochlear function in models.
• Significant challenges include transduction efficiency, immune responses, long-term stability, and ethical concerns, especially for embryonic gene therapy.

Conclusions:

• Preclinical studies demonstrate gene therapy potential for GJB2-related HL.
• Clinical application faces substantial scientific, technical, and ethical barriers, particularly for embryonic interventions.
• A cautious, multidisciplinary approach is crucial for safe and effective clinical translation.