Advances in cochlear gene therapies

Abstract

Purpose of review: Hearing loss is the most common sensory deficit and in young children sensorineural hearing loss is most frequently genetic in etiology. Hearing aids and cochlear implant do not restore normal hearing. There is significant research and commercial interest in directly addressing the root cause of hearing loss through gene therapies. This article provides an overview of major barriers to cochlear gene therapy and recent advances in preclinical development of precision treatments of genetic deafness.

Recent findings: Several investigators have recently described successful gene therapies in many common forms of genetic hearing loss in animal models. Elegant strategies that do not target a specific pathogenic variant, such as mini gene replacement and mutation-agnostic RNA interference (RNAi) with engineered replacement, facilitate translation of these findings to development of human therapeutics. Clinical trials for human gene therapies are in active recruitment.

Summary: Gene therapies for hearing loss are expected to enter clinical trials in the immediate future. To provide referral for appropriate trials and counseling regarding benefits of genetic hearing loss evaluation, specialists serving children with hearing loss such as pediatricians, geneticists, genetic counselors, and otolaryngologists should be acquainted with ongoing developments in precision therapies.

Figure 1.

Well-described delivery techniques for cochlear gene therapies. (A) A variety of delivery methods have been developed for delivery to the endolymphatic and perilymphatic compartments. Topical transtympanic delivery utilizes absorbable packing saturated in a gene therapy agent and is reliant on diffusion across the tympanic membrane and round window to achieve therapeutic levels of the drug within the cochlea (magenta cylinders). Transtympanic injection bypasses the tympanic membrane to inject within the middle ear space (large magenta needle). The remaining approaches (small magenta needles) offer direct delivery to the endolymphatic compartment, perilymphatic compartment (round window), or both (utricle, canalostomy, cochleostomy, utricle). B) Round window membrane injection combined with posterior or horizontal semicircular canal venting facilitates efficient, atraumatic vector transduction in murine models. In humans and non-human primates, a similar approach is proposed using a stapes footplate/oval window vent, which can be accessed via a transcanal tympanoplasty or mastoidectomy approach. CF: canal fenestration; In: incus; Ma: malleus; RW: round window; St: stapes; TM: tympanic membrane.

Figure 2.

Mechanisms of genetic disease and impacts on therapeutic strategies. (A) Autosomal recessive and autosomal dominant genetic disease arise via distinct mechanisms ranging from biallelic complete loss of protein function in autosomal recessive disease, to deleterious effects on the wild-type protein in dominant-negative disease. (B) General strategies for gene therapy. Gene replacement or gene editing may be used to treat disease mediated by loss of function or haploinsufficiency. In contrast, diseases with dominant-negative and gain-of-function mechanisms require suppression, disruption, or correction of the mutant allele. ASO: anti-sense oligonucleotide; CRISPR: clustered regularly interspaced short palindromic repeats; eWT: engineered wild-type allele; gRNA: guide RNA; HDR: homology-directed repair; NHEJ: non-homologous end joining; siRNA: small interfering RNA.