Sound strategies for hearing restoration

Abstract

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.

Figure 1

Anatomy of the inner ear. A) Schematic diagram of the human inner ear (24). The spiral shaped cochlea is shown with endolymph and perilymph fluids indicated in blue and yellow, respectively. The auditory organ known as the Organ of Corti is shown in red. Potential routes of entry for therapeutics are indicated: round window membrane (RWM) and cochleostomy (CO). B) Schematic diagram of a cross-section of the Organ of Corti. The three rows of outer hair cells and the one row of inner hair cells are colored in blue and the auditory neurons or spiral ganglion neurons are shown in green. C) Scanning electron micrograph of the Organ of Corti. The hair-cell cell-bodies are pseudo-colored blue. D) Scanning electron micrograph of the hair bundle of a single outer hair cell.

Figure 2

X-ray image of a cochlear implant in a human cochlea. This implant includes 29 stimulating electrodes. M, modiolus; RW, round window or entry point to the basal turn of the cochlea; BT, basal turn of the cochlea.

Figure 3

Confocal images of adult mouse cochlea transfected with AAV vectors of various serotypes. A) Inner hair cells (arrows) were positive for the transgene, green fluorescent protein (GFP), 7 days after transfection with AAV2. B) Cross-section of the Organ of Corti transfected with AAV8, counter stained for Sox2 (red) which marks supporting cells. High magnification view of hair cells transfected with AAV2 (C), AAV5 (D) or AAV6 (E), counter-stained with the nuclear marker, propidium iodide (red). Scale bars = 20 μm. Reprinted from Kilpatrick et al. (19).

Figure 4

Examples of stem cell-derived hair cell-like cells. A) Strategy used by Oshima et al. (45). B) Hair bundle generated from strategy shown in panel A. C) A family of mechanotransduction currents recorded from a stem-cell-derived hair cell-like cell. The hair bundle deflection protocol is shown above. D) Strategy used by Koehler et al. (47). E–F) Stem-cell derived otic vesicles and hair cells. F–G) Embryonic vestibular organ and hair cells. Immunomakers are color-coded at the bottom. Scale bar: 50 μm (E, G), 25 μm (F,H).