Inner Ear Gene Therapy: An Overview from Bench to Bedside

Abstract

Hearing loss represents a highly prevalent and debilitating sensory disorder affecting roughly one in five people worldwide. In a majority of patients with congenital hearing loss, genetic mutations cause the disease. Up until recently, therapeutic options for individuals with hearing loss were limited to hearing aids and different types of auditory implants. However, after numerous years of intensive basic and translational research, gene therapy strategies are now being investigated in clinical trials. First results show significant hearing improvement in treated patients, highlighting gene therapy's role as a promising treatment for certain forms of genetic hearing loss. In this article, we provide an overview of genetic hearing loss and inner ear gene therapy research including relevant strategies that have been established in animal models and will likely be investigated in human patients soon. Furthermore, we summarize and contextualize the novel findings of recently completed and ongoing clinical trials, and discuss future hurdles needed to be overcome to allow for a broad and safe clinical application of inner ear gene therapy.

Fig. 1

Overview of local vector delivery strategies to the inner ear. Local delivery techniques include transtympanic (TT) delivery to the tympanic membrane, intratympanic (IT) injection into the middle ear, intracochlear delivery via the round window membrane (RWM; yellow), a cochleostomy (CoS), or a canalostomy (CaS), and delivery through the cochlear aqueduct (CA) via the cerebrospinal fluid (CSF). The purpose and mechanism of a venting hole in the stapes footplate (blue) to allow even distribution along the cochlea is depicted using red and green arrows. This figure was created and adapted from Servier Medical Art (https://smart.servier.com/CC BY 4.0)