Abstract
Viral-mediated gene augmentation, silencing, or editing offers tremendous promise for the treatment of inherited and acquired deafness. Inner-ear gene therapies often require a safe, clinically useable and effective route of administration to target both ears, while avoiding damage to the delicate structures of the inner ear. Here, we examined the possibility of using a cisterna magna injection as a new cochlear local route for initiating binaural transduction by different serotypes of the adeno-associated virus (AAV2/8, AAV2/9, AAV2/Anc80L65). The results were compared with those following canalostomy injection, one of the existing standard inner ear local delivery routes. Our results demonstrated that a single injection of AAVs enables high-efficiency binaural transduction of almost all inner hair cells with a basal-apical pattern and of large numbers of spiral ganglion neurons of the basal portion of the cochlea, without affecting auditory function and cochlear structures. Taken together, these results reveal the potential for using a cisterna magna injection as a local route for binaural gene therapy applications, but extensive testing will be required before translation beyond mouse models.
Highlights
Hearing loss is currently the most frequent human sensory deficit and will affect almost one billion people worldwide in 2050 (World Health Organization, 2021)
To ensure the injected solution via the Cisterna magna (CM) route could enter into both left and right cochleae, we firstly compared the coloration of both cochleae following a single CM injection of fast green dye FIGURE 1 | recombinant genome for AAV2/8, AAV2/9, and AAV2/Anc80L65-CBA-enhanced green fluorescent protein (eGFP)
ITR: Inverted terminal repeat. (F): Representative confocal images showing eGFP positive cells in flat-mounted preparations of the apical portion of the left and right cochleae 15 days after CM injection with AAV2/Anc80L65. eGFP positive cells are in green, NF200 immunolabelled auditory nerve fibres and spiral ganglion neurons (SG, top and bottom images), Vglut three labelled inner hair cells and Phalloidin-labelled inner and outer hair cells (IHCs and OHCs respectively, top image) are in red
Summary
Hearing loss is currently the most frequent human sensory deficit and will affect almost one billion people worldwide in 2050 (World Health Organization, 2021). An underlying genetic cause is estimated to be responsible for deafness in 50–60% of affected persons (Angeli et al, 2012). No curative treatment is available for sensorineural hearing loss. The only existing options are sound amplification by hearing aids, and electrical stimulation of auditory nerves via cochlear implants. During the past decade, promising results have been obtained in cochlear gene therapy of mouse models of genetic deafness (Askew et al, 2015; Isgrig et al, 2017; Pan et al, 2017; Akil et al, 2019; Wu et al, 2021). A major challenge for the delivery of genetic therapeutic materials into the cochlea comes from the inner ear’s anatomical isolation; it is a small, complex structure
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