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Review
.2020 Jul 21;9(7):2309.
doi: 10.3390/jcm9072309.

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges

Affiliations
Review

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges

Sedigheh Delmaghani et al. J Clin Med..

Abstract

Hearing impairment is the most frequent sensory deficit in humans of all age groups, from children (1/500) to the elderly (more than 50% of the over-75 s). Over 50% of congenital deafness are hereditary in nature. The other major causes of deafness, which also may have genetic predisposition, are aging, acoustic trauma, ototoxic drugs such as aminoglycosides, and noise exposure. Over the last two decades, the study of inherited deafness forms and related animal models has been instrumental in deciphering the molecular, cellular, and physiological mechanisms of disease. However, there is still no curative treatment for sensorineural deafness. Hearing loss is currently palliated by rehabilitation methods: conventional hearing aids, and for more severe forms, cochlear implants. Efforts are continuing to improve these devices to help users to understand speech in noisy environments and to appreciate music. However, neither approach can mediate a full recovery of hearing sensitivity and/or restoration of the native inner ear sensory epithelia. New therapeutic approaches based on gene transfer and gene editing tools are being developed in animal models. In this review, we focus on the successful restoration of auditory and vestibular functions in certain inner ear conditions, paving the way for future clinical applications.

Keywords: AAV; CRISPR/Cas9; RNAi; antisense oligonucleotide; cochlea; gene therapy; genome editing; lipid nanoparticle-mediated delivery; sensorineural hearing loss; sensory disorders.

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Conflict of interest statement

The authors have no conflict of interest to disclose.

Figures

Figure 1
Figure 1
Mammalian inner ear anatomy and cochlear tonotopic organization. The mammalian inner ear consists of the vestibule (balance organs), which detect linear and angular accelerations, and the cochlea, the hearing organ, which detects sound waves. (A,B) The cochlea is made up of three fluid-filled compartments of differing ionic compositions—scala vestibuli (perilymph), thescala media (endolymph), and thescala tympani (perilymph). Sound conversion into electrical signals requires three major types of functional cells: hair cells (purple), supporting cells, and spiral ganglion neurons (yellow). (C) The auditory sensory organ, the organ of Corti, is made up of one row of highly organized inner hair cells (IHCs), three rows of outer hair cells (OHCs), flanked by various types of supporting cells. Along the cochlea, the hair cells, underlying basilar membrane (BM), surrounding, and overlying tectorial membrane (TM) are optimized to perceive specific and characteristic sound frequencies, defining a cochlear tonotopy that is preserved up to the auditory cortex. The structural and physical properties of the cochlea vary from base (shorter and stiffer cells) to apex (longer and more flexible cells). The cochlear base mainly perceives high-frequency tones (up to 20 kHz in humans), while the apex detects low-frequency sounds (20 Hz in humans). Scale bar in B, C: 1 μm.
Figure 2
Figure 2
Hearing loss causal origins and adapted therapeutic strategies. (A) Hearing loss, defined as mild (loss of 21 to 40 dB HL), moderate (41–70 dB HL loss), severe (71–90 dB HL loss), or profound (>90 dB HL loss), can be due to multiple causes: genetic, noise, and/or age. Whatever the cause, the hearing loss can start any time after birth, with varying degrees of progression and severity. (B) Various therapeutic approaches (gene supplementation, silencing, or gene editing) are being implemented either to protect, prevent and/or repair hearing loss, regenerate or replace inner ear cells.
Figure 3
Figure 3
Functional stratification genes/proteins causing human isolated deafness hearing loss. Based on their established role and characterization of corresponding animal models, the human deafness genes (DFNA DFNB DFNX AUNA) can be grouped into several functional categories: (1) hair bundle development and functioning, (2) synaptic transmission, (3) hair cell’s adhesion and maintenance, (4) cochlea ion homeostasis, (5) transmembrane or secreted proteins and extracellular matrix, (6) oxidative stress, metabolism and mitochondrial defects, and (7) transcriptional regulation. DFNAi (red) denotes autosomal-dominant forms of deafness with undefined locus number. The genes/loci in grey denote that they share several functional categories. More detailed information regarding the deafness causative genes are provided in Table S1.
Figure 4
Figure 4
Delivery approaches in the inner ear. Schematic representation of the human ear, illustrating methods used to deliver therapeutics into the inner ear. These include systemic (red) and middle ear (blue) indirect approaches, as well as endolymphatic sac delivery (light blue) and direct injections through different compartments of the inner ear (green): cochleostomy (scala media), vestibule (through utricle or semicircular canal), and cochlea (through round window membrane or oval window). Some pros and cons of each methods are highlighted in Table S2.
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