A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

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.

Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice

“…4, B and C). This distribution was consistent with the hypothesis that the virus enters the inner ear through the cochlear aqueduct ( 26 , 27 ). To evaluate the efficacy of this method in comparison with other types of systemic delivery, a subgroup of age-matched mice received AAV- eGFP intravenously.…”

Advancements and future prospects of adeno-associated virus-mediated gene therapy for sensorineural hearing loss

“… Blanc et al (2021) administered various AAV serotypes (AAV2/8, AAV2/9, AAV2/Anc80L65) through cisterna magna injection, resulting in high-efficiency binaural transduction affecting nearly all IHCs in a basal-to-apical pattern, as well as a substantial population of SGNs in the cochlea’s basal region. Remarkably, this intervention had no adverse effects on auditory function or cochlear structures ( Blanc et al, 2021 ). Further, Mathiesen et al (2023) investigated the potential of delivering gene therapy via the cerebrospinal fluid to restore hearing in adult deaf mice.…”

“…Multiple studies have suggested that AAV-mediated gene transfer to the fetal mouse otic vesicle can restore hearing in congenitally deaf mouse models lacking SLC26A4 or MSRB3 (Dulon et al, 2018;Kim et al, 2019). Blanc et al (2021) administered various AAV serotypes (AAV2/8, AAV2/9, AAV2/Anc80L65) through cisterna magna injection, resulting in high-efficiency binaural transduction affecting nearly all IHCs in a basal-to-apical pattern, as well as a substantial population of SGNs in the cochlea's basal region. Remarkably, this intervention had no adverse effects on auditory function or cochlear structures (Blanc et al, 2021).…”