Translating animal models to human therapeutics in noise-induced and age-related hearing loss

Abstract

Acquired sensorineural hearing loss is one of the most prevalent chronic diseases, and aging and acoustic overexposure are common contributors. Decades of study in animals and humans have clarified the cellular targets and perceptual consequences of these forms of hearing loss, and preclinical studies have led to the development of therapeutics designed to slow, prevent or reverse them. Here, we review the histopathological changes underlying age-related and noise-induced hearing loss and the functional consequences of these pathologies. Based on these relations, we consider the ambiguities that arise in diagnosing underlying pathology from minimally invasive tests of auditory function, and how those ambiguities present challenges in the design and interpretation of clinical trials.

Keywords: Age-related hearing loss; Cochlear drug therapy; Cochlear synaptopathy; Noise-induced hearing loss; Sensorineural hearing loss.

Figure 1:. Age related loss of hair cells in human vs. mouse.

Hair cell data are normalized and expressed as % survival. Age is normalized and expressed as % lifespan, using a value of 76 yrs for humans and 2.1 yrs for mouse, as detailed in Sergeyenko et al. (2013). Mouse data (CBA/CaJ) are replotted from our prior work (Sergeyenko et al., 2013); human data are from two studies (Bredberg, 1968; Wu et al., 2018) and represent values averaged across the entire cochlear spiral.

Figure 2:. Age-related primary neural degeneration in human vs. mouse.

Data are normalized as described for Figure 1. Human data are for IHCs and ANF peripheral axon counts, averaged across cochlear regions at half-octave intervals spanning the audiometric frequencies (0.25 to 8.0 kHz; Wu et al., 2018); mouse data are for IHCs and ANF synaptic counts averaged across 5 cochlear regions (5.6, 11.3, 22, 32 and 64 kHz), pooled from Parthasarathy and Kujawa (2018a) and Sergeyenko et al., (2013).