Systematic Review of AAV–Based Gene Therapy for Hereditary Deafness Presents Progress and Challenges

CLINICAL QUESTION

What is the current state of adeno-associated virus (AAV)-based gene therapy as therapy for hereditary deafness, particularly in terms of advancement and challenges in basic and clinical research?

BOTTOM LINE

AAV-based gene therapy represents a promising therapeutic approach for hereditary deafness.

BACKGROUND: Hereditary deafness is the most prevalent sensory deficit disorder, with more than 100 identified deafness-related genes. Gene therapy has emerged as a potential treatment for hereditary deafness, showing promising results. Due to the cochlea’s complex structure, however, precision gene therapy approaches are required for different genetic forms of deafness.

STUDY DESIGN: Systematic review

SETTING: State 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, China

SYNOPSIS: Researchers systematically summarized the preclinical and clinical research progress and practical challenges of using gene therapy for heredity deafness. In discussing the physiologic basis of heredity deafness, they described the complex cochlear structure; cited mutations in genetic material as a primary contributor to sensorineural hearing loss; noted that 148 genes associated with hereditary deafness have been identified; and described conventional clinical treatment strategies. They then discussed research on gene therapy for hereditary deafness, citing AAV as the predominant viral vector. They described the structure and capsid of AAV as well as basic research strategies in AAV-mediated hereditary deafness gene therapy—including gene replacement and gene editing tools—and drug delivery routes and methods. They then presented material from clinical studies, citing six ongoing trials worldwide that specifically focus on DFNB9 hearing loss. Safety concerns regarding AAV utilization were also reviewed. Finally, in discussing prospects of gene therapy programs for hereditary deafness, the authors emphasized that therapy development is predicated upon complete comprehension of underlying mechanisms driving disease pathogenesis and thus, DFNB9 currently remains the sole hereditary deafness disease for which gene therapy drugs have been successful in restoring hearing.

CITATION: Qi J, et al. AAV-mediated gene therapy restores hearing in patients with DFNB9 deafness. Adv Sci (Weinh). 2024;11:e2306788. doi: 10.1002/advs.202306788.