(0918) DFNA5, an Autosomal Dominant Hearing Loss: From Clinical Characteristics to Gene Editing Therapy Strategy

Introduction: DFNA5 is one form of autosomal dominant non-syndromic progressive hearing loss. Clinical presentation, hearing deterioration, and age of onset for DFNA5 mutations vary significantly. Understanding the characterization and prevalence of DFNA5-related hearing loss is necessary for the successful development and application of gene-based therapies and precision medicine approaches to DFNA5.

Methods: In this study, we begin by summarizing the auditory characteristics in patients with DFNA5 mutations. We explored the potential correlation between DFNA5 induced cell death processes and the onset of auditory hearing loss. Additionally, we propose the development of a groundbreaking inner ear organoids (IEOs), advocating its adoption as a more reliable alternative to the currently employed mouse model. Noteworthy is our provision of evidence-based recommendations for RNA base editing therapy strategies, emphasizing their potency as a therapeutic intervention with promising clinical applications.

Results: A total of 16 distinct DFNA5 mutations have been documented, with almost all leading to the exclusion of exon8 and the production of a truncated protein with constitutive activity. Notably, DFNA5 knockout animals do not adequately represent the phenotype, prompting a shift towards leveraging advancements in stem cell technology. Recent breakthroughs enable the creation of IEOs from human pluripotent stem cells carrying DFNA5 mutations, introduced via CRISPR/Cas9 techniques. In the realm of gene editing, targeting the exon7-exon9 junction locus with RNA-based systems offers a promising approach to degrade exon8-skipping transcripts, addressing the mutations responsible for hearing loss.

Conclusions: Taken together, this study has systematically summarized the DFNA5 clinic characteristics and potentially solved the bottleneck problem of the mouse model built-up. Additionally, our gene editing strategy provides novel hope and insight for treating patients with DFNA5-induced hearing loss and sheds some light on the genetic treatment for other DFNAs.