Age-related hearing loss (ARHL), clinically referred to as presbycusis, is one of the three most prevalent chronic medical conditions of our elderly, with the majority of persons over the age of 60 suffering from some degree of ARHL. The progressive loss of auditory sensitivity and perceptual capability results in significant declines in workplace productivity, quality of life, cognition and abilities to communicate effectively. Aldosterone is a mineralocorticoid hormone produced in the adrenal glands and plays a role in the maintenance of key ion pumps, including the Na-K(+)-Cl co-transporter 1 or NKCC1, which is involved in homeostatic maintenance of the endocochlear potential. Previously we reported that aldosterone (1 μM) increases NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 μM). In the current study we measured behavioral and electrophysiological hearing function in middle-aged mice following long-term systemic treatment with aldosterone. We also confirmed that blood pressure remained stable during treatment and that NKCC1 protein expression was upregulated. Pre-pulse inhibition of the acoustic startle response was used as a functional measure of hearing, and the auditory brainstem response was used as an objective measure of peripheral sensitivity. Long-term treatment with aldosterone improved both behavioral and physiological measures of hearing (ABR thresholds). These results are the first to demonstrate a protective effect of aldosterone on age-related hearing loss and pave the way for translational drug development, using aldosterone as a key component to prevent or slow down the progression of ARHL.

Objectives: There are no approved pharmacologic therapies for chronic sensorineural hearing loss (SNHL). The combination of CHIR99021+valproic acid (CV, FX-322) has been shown to regenerate mammalian cochlear hair cells ex vivo . The objectives were to characterize the cochlear pharmacokinetic profile of CV in guinea pigs, then measure FX-322 in human perilymph samples, and finally assess safety and audiometric effects of FX-322 in humans with chronic SNHL. Study Designs: Middle ear residence, cochlear distribution, and elimination profiles of FX-322 were assessed in guinea pigs. Human perilymph sampling following intratympanic FX-322 dosing was performed in an open-label study in cochlear implant subjects. Unilateral intratympanic FX-322 was assessed in a Phase 1b prospective, randomized, double-blinded, placebo-controlled clinical trial. Setting: Three private otolaryngology practices in the US. Patients: Individuals diagnosed with mild to moderately severe chronic SNHL (≤70 dB standard pure-tone average) in one or both ears that was stable for ≥6 months, medical histories consistent with noise-induced or idiopathic sudden SNHL, and no significant vestibular symptoms. Interventions: Intratympanic FX-322. Main Outcome Measures: Pharmacokinetics of FX-322 in perilymph and safety and audiometric effects. Results: After intratympanic delivery in guinea pigs and humans, FX-322 levels in the cochlear extended high-frequency region were observed and projected to be pharmacologically active in humans. A single dose of FX-322 in SNHL subjects was well tolerated with mild, transient treatment-related adverse events (n = 15 FX-322 vs 8 placebo). Of the six patients treated with FX-322 who had baseline word recognition in quiet scores below 90%, four showed clinically meaningful improvements (absolute word recognition improved 18–42%, exceeding the 95% confidence interval determined by previously published criteria). No significant changes in placebo-injected ears were observed. At the group level, FX-322 subjects outperformed placebo group in word recognition in quiet when averaged across all time points, with a mean improvement from baseline of 18.9% ( p = 0.029). For words in noise, the treated group showed a mean 1.3 dB signal-to-noise ratio improvement ( p = 0.012) relative to their baseline scores while placebo-treated subjects did not (−0.21 dB, p = 0.71). Conclusions: Delivery of FX-322 to the extended high-frequency region of the cochlea is well tolerated and enhances speech recognition performance in multiple subjects with stable chronic hearing loss.

In the clinical realm, we primarily rely on audiological measures for diagnosis and surveillance of sensorineural hearing loss (SNHL) and have limited therapeutic options. We have proposed a blood-based biomarker approach to overcome this challenge by measuring the outer hair cell’s (OHC) electromotile protein, prestin, in the blood. In a guinea pig model of cyclodextrin (CDX) ototoxicity, using western blots, we show that prestin in the blood may have several different forms and specifically the ~ 134 kDa form spikes after ototoxin ablation of OHCs. This form appears to be a glycosylated dimer likely secreted by the inner ear as exosomes reflecting increased expression after ototoxin exposure. These results suggest that the ~ 134 kDa dimer may serve as a biomarker for early detection of ototoxicity in the clinical setting. However, because prestin can still be measured in the blood after total ablation of OHCs, its ability to inform on OHC health is restricted to a narrow window after ototoxin-induced injury. Monitoring prestin, when using therapeutics with ototoxic properties, could guide dosage and administration schedule to minimize damage.

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.

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