Gene therapy for hereditary hearing loss: from molecular correction to clinical translation

Abstract

The hearing aids and cochlear implants were extremely effective in restoring auditory function; however, none of these devices provides any cure to the underlying molecular disease. Recently there has been an unprecedented advancement in the multiple fields including genomic diagnostics, viral vector engineering, methods of delivering therapeutic cargo into the inner ear, and genome editing technologies leading to the emergence of gene therapy for HHL as a potential treatment option in the clinic. To date, adeno-associated viral (AAV)-mediated gene augmentation approach has demonstrated the most successful results for treatment of HHL and otoferlin (OTOF) related deafness was the first molecular disease for which a gene therapy has proven the possibility to restore auditory function in human patients. Preliminary AAV-OTOF trials significantly improved hearing and speech perception in children with congenital deafness. Later studies have provided additional data regarding the applicability of AAV-based gene therapy for older patients and gained some insights on safety, dose, delivery and durability of the treatment effect. In addition to direct gene augmentation approaches such as viral delivery of transgenes, new gene therapy approaches have appeared: allele-specific silencing, antisense oligonucleotide-based therapies, base and prime editing, CRISPR/Cas9-mediated genome/RNA editing. However, the heterogeneity of mutations, narrow therapeutic windows, anatomy of the inner ear, vector tropism, immunological challenges, longevity of the effect and lack of standardized long-term outcomes criteria remain a problem. This review highlights molecular pathogenesis, potential therapeutic platforms, preclinical developments and latest clinical evidences for the use of gene therapy in HHL focusing on the transition of molecular cure to clinically-relevant auditory restoration.