Cochlear Gene Therapy for Sensorineural Hearing Loss: Current Status and Major Remaining Hurdles for Translational Success

Abstract

Sensorineural hearing loss (SNHL) affects millions of people. Genetic mutations play a large and direct role in both congenital and late-onset cases of SNHL (e.g., age-dependent hearing loss, ADHL). Although hearing aids can help moderate to severe hearing loss the only effective treatment for deaf patients is the cochlear implant (CI). Gene- and cell-based therapies potentially may preserve or restore hearing with more natural sound perception, since their theoretical frequency resolution power is much higher than that of cochlear implants. These biologically-based interventions also carry the potential to re-establish hearing without the need for implanting any prosthetic device; the convenience and lower financial burden afforded by such biologically-based interventions could potentially benefit far more SNHL patients. Recently major progress has been achieved in preclinical studies of cochlear gene therapy. This review critically evaluates recent advances in the preclinical trials of gene therapies for SNHL and the major remaining challenges for the development and eventual clinical translation of this novel therapy. The cochlea bears many similarities to the eye for translational studies of gene therapies. Experience gained in ocular gene therapy trials, many of which have advanced to clinical phase III, may provide valuable guidance in improving the chance of success for cochlear gene therapy in human trials. A discussion on potential implications of translational knowledge gleaned from large numbers of advanced clinical trials of ocular gene therapy is therefore included.

High Frequency of AIFM1 Variants and Phenotype Progression of Auditory Neuropathy in a Chinese Population

“…Hearing aids and cochlear implantations, which are typical intervention strategies for cochlear sensory hearing loss, have variable outcomes for AN cases depending on the affected lesion sites [3][4][5][6][7][8][9][10]. Gene therapy may provide possibility for the treatment of AN [11]. Since virally mediated gene expressions in almost 100% HCs are possible, the treatment of presynaptic AN is possible [12].…”

Recent development of AAV-based gene therapies for inner ear disorders

“…SCs are located at the bottom of the inner and OHCs, anchoring the sensory epithelium to the basilar membrane, thus playing a mechanical role in protecting and maintaining the surrounding environment for HCs. Some key deafness genes mainly express and have functions in SCs, such as GJB2, which affects the SC's gap junction and is the most common hereditary deafness gene [1,6,15,16]. In mammals, hair-cell loss due to environmental and genetic stress is thought to be permanent [17].…”

Congenital Middle Ear Malformation with Common Deafness Gene Mutation Analysis: A Review of 813 Profound Sensorineural Hearing Loss Child Patients

“…Genetic etiology could play an important role in pathogenesis of inner ear malformation. It is well known that genetic mutations could also play a major role in common middle ear diseases (http://hereditaryhearingloss.org/main.aspx?c=.HHH&n=86521) (Zhang et al, ). However, little has been investigated in the relationship between common deafness genes and middle ear abnormalities.…”