Approaches to Treat Sensorineural Hearing Loss by Hair-Cell Regeneration: The Current State of Therapeutic Developments and Their Potential Impact on Audiological Clinical Practice

Abstract

Sensorineural hearing loss (SNHL) is typically a permanent and often progressive condition that is commonly attributed to sensory cell loss. All vertebrates except mammals can regenerate lost sensory cells. Thus, SNHL is currently only treated with hearing aids or cochlear implants. There has been extensive research to understand how regeneration occurs in nonmammals, how hair cells form during development, and what limits regeneration in maturing mammals. These studies motivated efforts to identify therapeutic interventions to regenerate hair cells as a treatment for hearing loss, with a focus on targeting supporting cells to form new sensory hair cells. The approaches include gene therapy and small molecule delivery to the inner ear. At the time of this publication, early-stage clinical trials have been conducted to test targets that have shown evidence of regenerating sensory hair cells in preclinical models. As these potential treatments move closer to a clinical reality, it will be important to understand which therapeutic option is most appropriate for a given population. It is also important to consider which audiological tests should be administered to identify hearing improvement while considering the pharmacokinetics and mechanism of a given approach. Some impacts on audiological practice could include implementing less common audiological measures as standard procedure. As devices are not capable of repairing the damaged underlying biology, hair-cell regeneration treatments could allow patients to benefit more from their devices, move from a cochlear implant candidate to a hearing aid candidate, or move a subject to not needing an assistive device. Here, we describe the background, current state, and future implications of hair-cell regeneration research.

Fig. 1

Treatment with CHIR99021 + VPA (CV) leads to hearing improvement in an in vivo noise damage model. (A) Transtympanic injection of drug product into the middle ear of mice. (B) Animals designated to control-vehicle and CV groups had elevated thresholds at 24 hours and 5 weeks after noise exposure compared with pre-exposure baseline. Control n  = 37 animals, treated n  = 47 animals. (C) At 5 weeks after injection, CV animals had significantly lower hearing thresholds relative to control animals for four of the five frequencies tested. (D) The distribution of individual hearing recoveries was analyzed. Values represent the change in dB needed to elicit an auditory brain stem response (ABR), with positive values representing further threshold increases (further hearing loss) and negative values representing threshold decreases (improved hearing). The fraction of animals with a given ABR change from 24 hours to 5 weeks is shown for each frequency tested. The treated group had a higher incidence of animals with hearing improvement and the greatest individual recoveries. Values are presented as means ± standard error; * p  < 0.05; ** p  < 0.01; *** p  < 0.001; **** p  < 0.0001.

Fig. 2

Effects on hair cell number after treatment with CHIR99021 + VPA (CV). (A) Low magnification view of a healthy isolated cochlea showing complete rows of inner hair cells (IHCs) and outer hair cells (OHCs). (B) High magnification view of the region highlighted in (A) showing intact IHCs and OHCs in mid-frequency regions. (C) Cochleae of vehicle injected animals show widespread hair cell loss throughout the cochlea (apex and middle regions shown). (D) High magnification view of the region highlighted in (C) showing substantial absence of hair cells in mid-frequency regions, where a single IHC can be seen in the field of view (solid arrow). (E) Cochleae of CV-treated animals show a greater overall population of hair cells compared with vehicle-treated animals (apex and mid region shown). (F) High magnification view of the region highlighted in (E) showing a complete row of IHCs (solid arrow) and a population of OHCs (open arrow). (G) CV-treated cochleae (blue) show significantly more total hair cells, IHCs, and OHCs relative to vehicle-treated cochleae (gray). (H) The number of hair cells depicted as the percentage relative to an undamaged healthy cochlea. CV-treated cochleae (blue) show a significantly higher percentage of total hair cells, IHCs, and OHCs relative to vehicle-treated cochleae (gray). Scale bars, 100 µM low magnification, 20 µM high magnification. Values are presented as box-whisker plots; n  = 7 animals per group; * p  < 0.05; ** p  < 0.01.

Fig. 3

FX-322 Phase 1b word recognition (WR) results. WR scores at baseline and day 90. Four FX-322 subjects and zero placebo subjects showed clinically meaningful and statistically significant improvement. (Adapted from McLean et al, 2021. 46 )

Fig. 4

Word-in-Noise (WIN) performance in subjects treated with an intratympanic injection of placebo or FX-322. (A) Psychometric functions for WIN show no improvement from baseline to day 90 for placebo-treated subjects ( n  = 8). (B) FX-322 ( n  = 15)-treated subjects show improvement (mean, 95% confidence interval, p  = 0.012). (Adapted from McLean et al, 2021. 46 )

Fig. 5

Phase 2a trial testing different dosing paradigms of FX-322. All patients receive four injections weekly. Drug-treated subjects receive either one, two, or four doses of FX-322, with the remaining doses being placebo.