Reprogramming translation for rare disease therapy: challenges posed by large genes

Abstract

A recent study published in Nature by Jiang et al. delineates a breakthrough in the treatment of inherited hearing loss through gene therapy. 1 This study offers the most compelling clinical evidence so far that gene replacement therapy can safely restore signi fi cant hearing in children with OTOF-related deafness, with bene fi ts lasting up to 2.5 years, setting a new standard for treating inherited sensory disorders. The bespoke cell and gene therapy approach is revolutionizing precision medicine for genetically diverse diseases. The OTOF gene encodes otoferlin, a transmembrane protein involved in signal transduction that functions as a calcium sensor for synaptic vesicle fusion within the inner hair cells of the cochlea. This gene was linked to hereditary deafness in 1999 by Christine Petit ’ s group. 2 Here, in pediatric patients with autosomal recessive deafness caused by OTOF mutations, dual adeno-associated virus (AAV) – mediated delivery of the OTOF transgene was developed. 3 As the OTOF gene ’ s coding sequence exceeds the packaging capacity of a single AAV vector, the study employed a dual-AAV1 vector strategy to reconstitute the full-length OTOF coding sequence under the control of a Myo15 promoter in vivo following cochlear delivery. 3 In the earlier reported clinical trial, about 75% of children met both behavioral pure-tone audiometry (PTA) and auditory brainstem response (ABR) criteria. 3 Across multiple clinical centers, treated children demonstrated substantial and durable improvements in auditory function, including the restoration of ABRs, enhanced speech perception, and signi fi cant gains in sound detection and communication skills. Importantly, therapeutic bene fi ts were observed relatively quickly after treatment and persisted during extended follow-up periods, indicating stable transgene expression and enduring cochlear rescue. 1 Younger patients generally exhibited the most pronounced outcomes, underscoring the