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.

Keywords: cochlear gene therapy; genetic deafness; genetic mutations; hearing restoration; preclinical trials; review; sensorineural hearing loss; viral-mediated gene expression.

Figure 1

Three injection routes commonly used in cochlear gene delivery. PSCC, posterior semicircular canal; LSCC, lateral semicircular canal; ASCC, anterior semicircular canal; RW, round window; OW, oval window; ST, Scala tympani; SM, Scala media; SV, Scala vestibuli.

Figure 2

Stages of degeneration in the cochlea may greatly affect the likelihood of success for cochlear gene therapies. Illustration of proposed four stages of disease progression in the cochlea caused by genetic mutations, as suggested by ocular gene therapy studies (Dalkara et al., 2016). Healthy cochlea is composed of health sensory cells (both IHCs and OHCs), supporting cells and cells in the SV. Deafness mutations may give rise to no significant cell death (A, defined as stage I), cell death primarily in (or started from) outer HCs (B, stage II), followed progressively and more severe degeneration stages of III (C, both inner and outer HCs are lost) and IV (D, all sensory and supporting cells are lost, leaving a layer of non-specific epithelial cells in the organ of Corti. SV is severely degenerated). According to results obtained from human clinical trials of ocular gene therapy, diseases at the stage III or stage IV have little chance for a successful outcome for gene therapy (Dalkara et al., 2016). In these cases, new strategies for applying gene therapy to restore hearing will need to be explored, and one is suggested in Figure 3.

Figure 3

A mechano-genetics approach for treating SNHL. Degeneration in the cochlea caused by many deafness gene at the adult stage will be in stages III and IV (Figure 2), which is treatable by CIs that directly excite SGNs by extracellular electrical field potential. This figure gives an illustration of possible outcome in degenerated organ of Corti after receiving gene therapy to express both neurotrophic (e.g., BDNF) and mechano-sensitive channels (MSCs). Peripheral fibers of survived SGNs are supposed to be induced to grow into the area of remaining basilar membrane. The MSCs are virally-expressed in the cell membrane of SGNs. These MSCs are normally attached to microtubes via ankyrin repeats (boxed insert), and the MSCs are opened directly by mechanical stimuli to the cell membrane (Zhang et al., 2015). It is hypothesized, as an alternative gene therapy method, that virally-expressed MSCs may render SGNs directly respond to vibration of the basilar membrane by firing action potentials. The advantage of this approach is that it requires similar cellular survival condition as that in the cochlea of CI patients.