Gene therapy for hearing loss

Abstract

Sensorineural hearing loss (SNHL) is the most common sensory disorder. Its underlying etiologies include a broad spectrum of genetic and environmental factors that can lead to hearing loss that is congenital or late onset, stable or progressive, drug related, noise induced, age related, traumatic or post-infectious. Habilitation options typically focus on amplification using wearable or implantable devices; however exciting new gene-therapy-based strategies to restore and prevent SNHL are actively under investigation. Recent proof-of-principle studies demonstrate the potential therapeutic potential of molecular agents delivered to the inner ear to ameliorate different types of SNHL. Correcting or preventing underlying genetic forms of hearing loss is poised to become a reality. Herein, we review molecular therapies for hearing loss such as gene replacement, antisense oligonucleotides, RNA interference and CRISPR-based gene editing. We discuss delivery methods, techniques and viral vectors employed for inner ear gene therapy and the advancements in this field that are paving the way for basic science research discoveries to transition to clinical trials.

Figure 1.

Inner ear delivery of gene therapy. Shown are the major routes by which gene therapy can be delivered to the inner ear. With the RWM approach, a small needle is used to pierce the RWM and deliver vector directly into the perilymph. A ‘canalostomy’ is done by drilling a hole into a semicircular canal (usually the posterior canal) and inserting a canula into the hole. Vector is delivered into both endolymph and perilymph in one of two directions depending on the orientation of the cannula. A cochleostomy requires a hole in the bony labyrinth between round window and basal turn of cochlea. Vector is delivered into endolymph. The RWM + CF technique combines RWM injection with a CF, which functions as a vent to allow egress of fluid (red, endolymph; yellow, perilymph; blue arrow, expected flow of injected vectors through cochlea when RWM + CF is done; PSCC, posterior semicircular canal; ASCC, anterior semicircular canal; LSCC, lateral semicircular canal; OW, oval window; RW, round window).