Emerging Gene Therapies for Genetic Hearing Loss

Abstract

Gene therapy, or the treatment of human disease using genetic material, for inner ear dysfunction is coming of age. Recent progress in developing gene therapy treatments for genetic hearing loss has demonstrated tantalizing proof-of-principle in animal models. While successful translation of this progress into treatments for humans awaits, there is growing interest from patients, scientists, clinicians, and industry. Nonetheless, it is clear that a number of hurdles remain, and expectations for total restoration of auditory function should remain tempered until these challenges have been overcome. Here, we review progress, prospects, and challenges for gene therapy in the inner ear. We focus on technical aspects, including routes of gene delivery to the inner ear, choice of vectors, promoters, inner ear targets, therapeutic strategies, preliminary success stories, and points to consider for translating of these successes to the clinic.

Recent Advancements in Gene and Stem Cell‐Based Treatment Modalities: Potential Implications in Noise‐Induced Hearing Loss

“…Despite the elegant potential of gene therapy and stem cell‐based therapy, one potential problem that needs to be addressed is determining the mode and vehicle of delivery. The three main approaches explored for gene therapy so far are (1) direct injection into the perilymphatic space via the round window membrane, (2) via the oval window, and finally (3) to the scala tympani or scala vestibuli via cochleostomy (Shu et al, ; Ahmed et al, ). The integrity of the blood‐labyrinthine barrier should theoretically contain the therapeutic agent concentration within the cochlea, and the advection flow through the organ should facilitate even distribution of the agent to distal regions within the inner ear as well (Ahmed et al, ).…”

“…The three main approaches explored for gene therapy so far are (1) direct injection into the perilymphatic space via the round window membrane, (2) via the oval window, and finally (3) to the scala tympani or scala vestibuli via cochleostomy (Shu et al, ; Ahmed et al, ). The integrity of the blood‐labyrinthine barrier should theoretically contain the therapeutic agent concentration within the cochlea, and the advection flow through the organ should facilitate even distribution of the agent to distal regions within the inner ear as well (Ahmed et al, ). But with any of these approaches, disrupting the high potassium content of the endolymph to the perilymphatic space is a very real possibility, and may compromise the function of these compartments.…”

“…Viral vectors have distinguished themselves as promising delivery systems, demonstrating effectiveness in animal models. Among many explored, adenovirus (Adv), Adeno‐associated viruses (AAV), and lentiviruses have shown efficacy in in vitro and in vivo settings (Shu et al, ; Ahmed et al, ). However, their safety and efficacy have yet to be confirmed in human trials, as the risk of unforeseen mutagenesis and long‐term cellular effect at the site of transplantation is a speculative possibility.…”

Split otoferlins reunited

“…Because otoferlin expression in the cochlea is restricted to a subset of cells known as inner hair cells (IHCs), therapeutic strategies for overcoming the consequences of OTOF mutations need only target a quarter of cochlear hair cells, ~4,000 in humans, ~1,000 in mice. Luckily, in this case, AAV vectors provide a strong advantage, since a number of different AAV serotypes have been identified that efficiently target cochlear inner hair cells (IHCs; Ahmed et al , ). Another important advantage for development of OTOF gene therapy is the fact that otoferlin is not required for development or survival of inner hair cells.…”

“… Gene therapy for genetic hearing loss is a nascent field with just a handful of studies published to date that demonstrate proof‐of‐concept recovery of auditory function (reviewed in Ahmed et al , ; Lustig & Akil, ). One challenge that faces the inner ear field, as well as the broader gene therapy field, is the need to deliver large gene sequences despite the limited genetic capacity (~4.5 kB) of delivery vehicles such as adeno‐associated viral vectors ( AAV ).…”