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Combined AAV-mediated specific Gjb2 expression restores hearing in DFNB1 mouse models
Qiuhan Sun1, Fangzhi Tan2, Liyan Zhang1
1State Key Laboratory of Digital Medical Engineering, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, School of Medicine, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing 210096, China; Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.
Gene therapy using adeno-associated virus (AAV) vectors shows promise for treating GJB2-related hereditary deafness. A novel AAV combination effectively restored hearing in mice and demonstrated safety in large animals, paving the way for clinical application.
Area of Science:
- Genetics
- Otolaryngology
- Molecular Biology
Background:
- Mutations in the GJB2 gene, encoding connexin 26, are a primary cause of autosomal recessive hereditary deafness.
- Adeno-associated virus (AAV)-mediated gene therapy offers a potential treatment for hearing loss, but existing vectors lack specificity and efficiency.
Purpose of the Study:
- To develop a more specific and efficient AAV-mediated gene therapy strategy for GJB2-related hereditary deafness.
- To evaluate the safety and efficacy of the developed gene therapy in preclinical models, including large animals.
Main Methods:
- Screening of AAV serotypes for targeted delivery to GJB2-expressing cells.
- Development of a specific promoter (SCpro) to control GJB2 expression and prevent ototoxicity.
- Co-administration of AAV1 and AAV-ie vectors carrying exogenous GJB2 driven by SCpro in GJB2-deficient mice, Bama miniature pigs, and cynomolgus monkeys.
Main Results:
- Co-administration of AAV1 and AAV-ie effectively targeted GJB2-expressing cells.
- The SCpro promoter prevented AAV-induced ototoxicity.
- Restored hearing function in GJB2-deficient mice.
- Demonstrated successful transduction in the cochleae of Bama miniature pigs.
- Showed no hearing impairment or significant systemic toxicity in cynomolgus monkeys.
Conclusions:
- The combined AAV system with the SCpro promoter is an efficient and safe strategy for GJB2 gene therapy.
- This approach holds significant potential for future clinical applications in treating hereditary deafness.
