Towards the Clinical Application of Gene Therapy for Genetic Inner Ear Diseases

Abstract

Hearing loss, the most common human sensory defect worldwide, is a major public health problem. About 70% of congenital forms and 25% of adult-onset forms of deafness are of genetic origin. In total, 136 deafness genes have already been identified and there are thought to be several hundred more awaiting identification. However, there is currently no cure for sensorineural deafness. In recent years, translational research studies have shown gene therapy to be effective against inherited inner ear diseases, and the application of this technology to humans is now within reach. We provide here a comprehensive and practical overview of current advances in gene therapy for inherited deafness, with and without an associated vestibular defect. We focus on the different gene therapy approaches, considering their prospects, including the viral vector used, and the delivery route. We also discuss the clinical application of the various strategies, their strengths, weaknesses, and the challenges to be overcome.

Keywords: AAV; gene therapy; hearing impairment; vestibular defect.

Figure 1

Route of administration for inner ear gene therapy. Routes of administration evaluated in mouse models (left panel), and potential delivery routes in humans (surgical view through the middle ear cavities, right panel). The most widely used delivery route is injection through the round window membrane (1), which is possible in both mice and humans, followed by the posterior semicircular canal (SCC, 2) in mice, which is potentially equivalent to a lateral SCC injection (3) in humans. Other techniques that have been evaluated in mice include injection into the endolymphatic sac (4) and cochleostomy (5). Injection through the oval window (6) is possible in humans, but not in mice, due to the persistence of the stapedial artery in rodents.