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Refining surgical techniques for efficient posterior semicircular canal gene delivery in the adult mammalian inner ear with minimal hearing loss.

ABSTRACT: Hearing loss is a common disability affecting the world's population today. While several studies have shown that inner ear gene therapy can be successfully applied to mouse models of hereditary hearing loss to improve hearing, most of these studies rely on inner ear gene delivery in the neonatal age, when mouse inner ear has not fully developed. However, the human inner ear is fully developed at birth. Therefore, in order for inner ear gene therapy to be successfully applied in patients with hearing loss, one must demonstrate that gene delivery can be safely and reliably performed in the mature mammalian inner ear. In this study, we examine the steps involved in posterior semicircular canal gene delivery in the adult mouse inner ear. We find that the duration of perilymphatic leakage and injection rate have a significant effect on the post-surgical hearing outcome. Our results show that although AAV2.7m8 has a lower hair cell transduction rate in adult mice compared to neonatal mice at equivalent viral load, AAV2.7m8 is capable of transducing the adult mouse inner and outer hair cells with high efficiency in a dose-dependent manner.

SUBMITTER: Zhu J

PROVIDER: S-EPMC8458342 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Superior semicircular canal dehiscence (SCD), which is characterized by a "third mobile window" in the inner ear, causes various vestibular and auditory symptoms and signs. Surgical plugging of the superior semicircular canal (SC) can eliminate the symptoms associated with increased perilymph mobility due to the presence of the third window. However, the natural course of vestibular function after surgical plugging remains unknown. Therefore, we explored longitudinal vestibular function after surgery in 11 subjects with SCD who underwent SC plugging using the middle cranial fossa approach. Changes in vestibulo-ocular reflex (VOR) gain in all planes were measured over 1 year with the video head impulse test. We also evaluated surgical outcomes, including changes in symptoms, audiometric results, and electrophysiological tests, to assess whether plugging eliminated third mobile window effects. The mean VOR gain for the plugged SC decreased from 0.81 ± 0.05 before surgery to 0.65 ± 0.08 on examinations performed within 1 week after surgery but normalized thereafter. Four of seven subjects who were able to perform both VOR tests before surgery and immediately after surgery had pathologic values (SC VOR gain < 0.70). Conversely, the mean VOR gain in the other canals remained unchanged over 1 year. The majority of symptoms and signs were absent or markedly decreased at the last follow-up evaluation, and no complications associated with the surgery were reported. Surgical plugging significantly attenuated the air-bone gap, in particular at low frequencies, because of increased bone conduction thresholds and deceased air conduction thresholds. Moreover, surgical plugging significantly increased vestibular-evoked myogenic potential thresholds and decreased the ratio of summating potential to action potential in plugged ears. Postoperative heavily T2-weighted images were available for two subjects and showed complete obliteration of the T2-bright signal intensity in the patent SC lumen in preoperative imaging based on filling defect at the site of plugging. Our results suggest that successful plugging of dehiscent SCs is closely associated with a transient, rather than persistent, disturbance of labyrinthine activity exclusively involved in plugged SCs, which may have clinical implications for timely and individualized vestibular rehabilitation.

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Refining surgical techniques for efficient posterior semicircular canal gene delivery in the adult mammalian inner ear with minimal hearing loss.

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