Gene Therapy for Deafness: Updates in Models, the Clinic and Challenges Ahead

The rapid advancements in high-throughput sequencing have facilitated the identification of pathogenic variants and the discovery of novel genes, bringing in the era of precision medicine. Hearing loss has benefited from this approach due to its genetic and phenotypic heterogeneity, with over 200 deafness-related genes found to date. Most recently, gene therapy clinical trials in children with pathogenic variants in the OTOF gene have demonstrated significant improvements in hearing thresholds. As gene therapy becomes a reality for human deafness, it is critical to identify pathogenic variants in each population to implement therapy as it becomes available for each gene. We analyzed electronic medical records (EMRs) from the Maccabi HMO Biobank to identify hearing impaired individuals, obtained DNA and performed whole-exome sequencing using an Illumina platform. To analyze novel variants, we developed PredHL, a machine-learning model that predicts the impact of pathogenic variants at the protein level by capturing energetic and physico-chemical changes caused by disease mutations. Gene therapy is being implemented on mouse models of human deafness. We successfully restored hearing and balance in a CLIC5 mouse model for deafness. Ultimately, these efforts will enhance patient management and rehabilitation.