Hearing loss: The final frontier of pharmacology

Abstract

Despite a prevalence greater than cancer or diabetes, there are no currently approved drugs for the treatment of hearing loss. Research over the past two decades has led to a vastly improved understanding of the cellular and molecular mechanisms in the cochlea that lead to hearing deficits and the advent of novel strategies to combat them. Combined with innovative methods that enable local drug delivery to the inner ear, these insights have paved the way for promising therapies that are now under clinical investigation. In this review, we will outline this renaissance of cochlear biology and drug development, focusing on noise, age-related, and chemotherapy-induced hearing dysfunction.

Keywords: cochlea; hair cell; hearing loss; neurotrophin; ototoxicity; regeneration; synaptopathy.

FIGURE 1

Chemical structures of small molecules in clinical development for hearing loss.

FIGURE 2

Auditory structures and cochlear anatomy. (A) Sound transmission within the cochlea occurs when fluid movement causes deflection of the basilar membrane upon which the mechanosensory inner and outer hair cells (IHCs and OHCs, respectively) sit. This produces deflections of the hair cell stereocilia to open spring‐gated ion channels at their tips resulting in depolarization of the hair cells and neurotransmitter release onto the spiral ganglion neurons (SGNs) sending signals through the VIII cranial nerve to the brain. (B) Intratympanic (IT) injection is a non‐invasive localized delivery strategy which targets the inner ear by injecting through the tympanic membrane to deliver drug to the surface of the permeable round window membrane (RWM) enabling drug to diffuse or move via active transport mechanisms into the cochlea to reach the sensory cells of the auditory periphery.

FIGURE 3

Key mechanisms in hair cell regeneration. Hair cell regeneration occurs by one of two complimentary mechanisms: direct transdifferentiation, in which a support cell directly converts into a new hair cell, and mitotic proliferation, in which support cells divide producing two daughter cells, one or more of which can then differentiate into a new hair cell. Some of the key pathways and genes known to play a role in either proliferation or differentiation of HCs during regeneration and which have been targets of therapeutic strategies include Wnt/β‐catenin signaling, the Notch signaling pathway, P27kip1, Gfi, MYC, and most recently epigenetic regulation by HDAC inhibitors and others.

FIGURE 4

Cochlear synaptopathy and therapeutic approaches for restoring ribbon synapses using neurotrophic modulators. (A) Ribbon synapses that connect IHCs (turquoise) with SGN afferent fibers are vulnerable to ototoxic agents, noise trauma, and aging. Specifically, the high‐threshold modiolar fibers (yellow) are most susceptible to these insults and show early degeneration and retraction from the IHCs resulting in speech‐in‐noise hearing difficulty. (B) Binding and homodimerization of Trk receptors (TrkB or C) with their neurotrophic ligands (BDNF, or NT‐3, respectively) results in downstream activation of the AKT, CAMK, and ERK signaling pathways which play important roles in cell survival, synaptic plasticity, axonal/dendritic growth, and neural differentiation during development and repair, making them key targets for therapeutic intervention.

FIGURE 5

Cellular targets and therapeutic strategies for cisplatin‐induced ototoxicity in the cochlea. (A) Within the cochlea, platinum‐based chemotherapeutic agents can induce damage or cell death within cells of the stria vascularis (bright blue), the inner (dark blue), and outer hair cells (turquoise), as well as the spiral ganglion neurons (yellow) that innervate the hair cells, damage to any of which can contribute to hearing loss. (B) Many strategies have been evaluated to mitigate this ototoxic hearing loss, some of the mechanisms reported in the literature which have shown promise include channel blockers to prevent cisplatin from entering vulnerable cell types, anti‐inflammatory agents, antioxidants, anti‐apoptotic agents, and cisplatin binding/scavenging compounds.