Milestones toward cochlear gene therapy for patients with hereditary hearing loss

Abstract

A number of genes are reportedly responsible for hereditary hearing loss, which accounts for over 50% of all congenital hearing loss cases. Recent advances in genetic testing have enabled the identification of pathogenic variants in many cases, and systems have been developed to provide personalized treatment based on etiology. Gene therapy is expected to become an unprecedented curative treatment. Several reports have demonstrated the successful use of cochlear gene therapy to restore auditory function in mouse models of genetic deafness; however, many hurdles remain to its clinical application in humans. Herein, we focus on the frequency of deafness genes in patients with congenital and late-onset progressive hearing loss and discuss the following points regarding which genes need to be targeted to efficiently proceed with clinical application: (a) which cells' genes are expressed within the cochlea, (b) whether gene transfer to the targeted cells is possible using vectors such as adeno-associated virus, (c) what phenotype of hearing loss in patients is exhibited, and (d) whether mouse models exist to verify the effectiveness of treatment. Moreover, at the start of clinical application, gene therapy in combination with cochlear implantation may be useful for cases of progressive hearing loss.

Keywords: adeno‐associated virus; cochlear implant; electric‐acoustic stimulation; gene therapy; genetic deafness; hereditary hearing loss.

FIGURE 1

The frequency of genetic mutations found in 1120 Japanese patients with hearing loss (Nishio et al., 2015). Relatively prevalent deafness genes, such as GJB2, CDH23, and SLC26A4, are described

FIGURE 2

The expression sites of causal genes of hearing loss in the cochlea (Nishio et al., 2015). The cochlea contains various types of cells that have distinct functions. The genes responsible for genetic deafness expressed in each cell type are shown

FIGURE 3

Inner ear schematic showing established delivery routes. Vector delivery into the perilymph via a round window membrane (RWM) or a RWM combined with a semicircular canal fenestration (CF); vector delivery into the endolymph via cochleostomy or canalostomy. OW indicates oval window

FIGURE 4

The schema of hybrid gene therapy based on a combination with cochlear implants. In patients with high‐frequency hearing loss, cochlear implants (CIs) improve hearing ability, while the natural course of low‐frequency hearing loss is observed (upper). Residual hearing can be preserved by performing cochlear gene therapy through CIs (lower)