Sound Strategies for Hearing Restoration

Background Sensorineural hearing loss is the most common sensory deficit in the world, with nearly 300 million affected individuals. The problem is multifactorial and can arise from damage or death of the primary sensory cells or the inner-ear neurons that relay auditory information to the brain. The inner-ear sensory cells and neurons can be damaged by environmental insult (such as exposure to infectious agents, drugs such as aminoglycoside antibiotics or chemotherapeutics, or overexposure to loud sounds) or by a host of genetic factors. Because mature inner ears lack the capacity for self-repair, the cellular damage is permanent. In addition to acquired hearing loss, more than 300 genetic loci have been linked to hereditary hearing loss, with about 70 of the causative genes identified. Eighty percent of genetic hearing loss is recessive, with the rest inherited as a dominant trait. More subtle genetic defects that cause a predisposition toward age-related hearing loss are poorly understood. Unfortunately, there is no cure for acquired, inherited, or age-related hearing loss. Native and engineered mechanosensory hair cells of the mammalian inner ear. Airborne sound vibrations, funneled through the external ear, are relayed through the middle ear to the inner ear, where they propagate as sound pressure waves in the fluid-filled spaces of the cochlea. The human cochlea contains ~16,000 sensory hair cells that convert sound pressure into electrical signals. (A) Hair cells are crowned with mechanosensory organelles composed of 50 to 100 actin-filled microvilli, organized into staircase arrays known as hair bundles. Extracellular linkages couple microvilli and ensure that the entire bundle responds to sound stimulation with coherent motion. (B) Bundle motion focuses sound energy onto the mechanotransduction apparatus, which includes one or two mechanically gated ion channels (50 to 100 per cell). According to the prevailing model, the channel complex is anchored to the actin core on the intracellular side at the tip of the shorter microvillus. On the extracellular side, there is a tip-link that extends to the side of the adjacent taller neighbor. At the top end, the tip-link is tethered to intracellular motor molecules that regulate tension within the apparatus. Sound-induced changes in tip-link tension modulate the open probability of the mechanosensitive channels, which in turn modulate the flow of electric current into the cell. Disruption of the sensory hair bundle by genetic mutation, loud sounds, or ototoxic drugs can lead to hair-cell dysfunction and deafness. Strategies to restore hair cells and mechanosensory function are being developed to treat patients with neurosensory hearing loss. [Illustrated by B. Pan] (C) Scanning electron microscopy image of a native hair bundle from the mouse inner ear. [Reprinted from J. R. Holt et al., Cell 108, 371–381 (2002) by permission from Elsevier] (D) A hair-cell–like cell generated via a gene-therapy strategy and viral-mediated delivery of the transcription factor Atoh1 into the inner ear of a deaf guinea pig. [Reprinted from Kawamoto et al., J. Neurosci. 23, 4395–4400 (2003) by permission of the Society for Neuroscience] (E) A hair-cell–like cell generated from embryonic stem cells and a stepwise differentiation protocol. Similar cells generate functional mechanosensitive responses to microvilli deflection. [Reprinted from Oshima et al., Cell 141, 704–716 (2010) by permission from Elsevier] Advances Efforts to restore and repair damaged inner-ear cells have intensified over the past 10 years. Thus far, a major thrust has been to adapt three biological strategies for use in the inner ear: gene therapy, stem-cell therapy, and molecular therapy. Using these approaches, researchers have restored sensory function at the cellular level in animal models of human hearing loss. A few reports suggest functional recovery at the systems and behavioral levels, although caveats remain. Outlook As the population continues to age and expand, so will the number of patients who suffer from clinically serious hearing loss. As such, the need for a deeper and comprehensive understanding of hearing-loss therapies is more pressing than ever. Although the pace of progress is accelerating and clinical trials are on the horizon, it is clear that there are still a number of hurdles to overcome. Overall, there are reasons to be both cautious and optimistic as we attempt to repair and regenerate one of nature’s most exquisite mechanosensory devices: the human inner ear. Hearing Aid Many millions of people across the globe are subject to hearing loss. Géléoc and Holt (10.1126/science.1241062) review recent developments in potential therapeutic strategies to restore inner-ear function in patients with acquired or genetic forms of deafness. While challenges remain, fundamental research in molecular, gene, and stem-cell therapies has enabled progress toward developing alternatives to conventional, sound amplification–based prostheses. Hearing loss is the most common sensory deficit in humans, with some estimates suggesting up to 300 million affected individuals worldwide. Both environmental and genetic factors contribute to hearing loss and can cause death of sensory cells and neurons. Because these cells do not regenerate, the damage tends to accumulate, leading to profound deafness. Several biological strategies to restore auditory function are currently under investigation. Owing to the success of cochlear implants, which offer partial recovery of auditory function for some profoundly deaf patients, potential biological therapies must extend hearing restoration to include greater auditory acuity and larger patient populations. Here, we review the latest gene, stem-cell, and molecular strategies for restoring auditory function in animal models and the prospects for translating these approaches into viable clinical therapies.