Is there an unmet medical need for improved hearing restoration?

Abstract

Hearing impairment, the most prevalent sensory deficit, affects more than 466 million people worldwide (WHO). We presently lack causative treatment for the most common form, sensorineural hearing impairment; hearing aids and cochlear implants (CI) remain the only means of hearing restoration. We engaged with CI users to learn about their expectations and their willingness to collaborate with health care professionals on establishing novel therapies. We summarize upcoming CI innovations, gene therapies, and regenerative approaches and evaluate the chances for clinical translation of these novel strategies. We conclude that there remains an unmet medical need for improving hearing restoration and that we are likely to witness the clinical translation of gene therapy and major CI innovations within this decade.

Keywords: clinical translation; cochlear implant; gene therapy; hearing impairment; optogenetic hearing restoration.

Figure 1. Normal hearing and hearing impairment

Schematic illustration of the auditory periphery. Soundwaves are funneled by the pinna of the outer ear into the ear canal, vibrate the tympanic membrane, which is connected via three small ossicles (malleus, incus, and stapes) to the oval window of the snail‐shaped cochlea. The cochlea is organized in a tonotopic manner, meaning low frequencies are represented in the apical turn and high frequencies towards the base. Sound encoding takes place in spiral ganglion neurons (SGNs) that are driven by glutamatergic transmission at ribbon synapses with inner hair cells (IHCs), which are part of the organ of Corti (inset). IHCs are each innervated by ~ 5–30 SGNs, which are located at some distance to the hair cells in the Rosenthal's canal forming the auditory nerve heading towards the brain. Three rows of outer hair cells (OHC) provide cochlear amplification and compression. Hearing impairment caused by alterations of outer and/or middle ear is defined as conductive hearing loss, while sensorineural hearing loss describes dysfunctional or missing hair cells. Lesions of the central auditory system cause central hearing loss.

Figure 2. Normal and electrical hearing

(A) Acoustic hearing: Sound pressure waves in the air travel along the ear canal and are relayed via the ossicles into the intracochlear fluid, where they are decomposed in a frequency‐dependent manner (center). A traveling pressure wave along the basilar membrane activates mechanosensitive hair cells (red) in the organ of Corti at the respective cochlear location and thereby starts the information flow in the auditory system via synaptic transmission from IHCs to SGNs (right). The precise frequency mapping (tonotopy) is visualized through the basilar membrane (see color bar). (B) Electrical hearing: Acoustic signals are analyzed by an external processor, which extracts predominant frequencies and corresponding amplitudes of the signal. The extracted frequencies are mapped to distinct stimulation sites, so that SGNs around the tonotopic region that would be activated by hair cells for a given sound frequency in physiological hearing (A) are then directly activated by the implanted electrodes (B).

Figure 3. Patient perspective on the importance of improved hearing restoration

Result of a survey conducted among 79 eCI patients with eCI. Participants ranked the importance of the hearing experience from 0 (not important) up to 10 (very important), and responses were separated into 4 categories of importance: not important (0 to 2), less important (3 to 5), important (6 to 8), and very important (9 to 10). The majority of respondents rated hearing of natural sounds, speech, phone calls, and music as quite important. In addition, fast rehabilitation after implantation seems relevant to users.

Figure 4. Optogenetic hearing restoration will likely build on combining AAV‐mediated gene therapy for ChR expressing in SGNs with waveguide‐based oCI for spectrally selective SGN stimulation

Illustration of a future oCI consisting of a red multibeam waveguide, a sound processor with a newly developed sound coding strategy, which enables complete exploitation of the optical stimulation. In front a catheter and a vial carrying the AAV symbolizing the need for gene therapy.

Figure 5. Principle of optogenetic hearing restoration

Top: An emitter array is placed in scala tympani and provides spatially confined optical stimulation of ChR expressing SGNs (inset shows immunofluorescently marked ChR (green) expressing SGNs, identified by context marker parvalbumin (magenta) in rodents). Bottom: demonstration of near physiological spectral selectivity. Confined or spectral selective midbrain activity for optogenetic (middle panel), acoustic (left), but not for electrical (right) stimulation with poor spectral selectivity.