Gene therapy restores auditory function and rescues damaged inner hair cells in an aged Vglut3 knockout mouse model.

Vesicular glutamate transporter 3 (VGLUT3) is prominently expressed in the inner hair cells of the cochlea, playing a vital role in auditory signal transmission to the brain. Previous studies have shown that Vglut3 gene knockout in mice causes severe sensorineural hearing loss without affecting hair cell integrity. However, the cochlear structure of the aged Vglut3 remains inadequately explored.

Rapid cochlear gene therapy in adult deaf mice: rescue via AAV8 achieves day-1 hearing restoration.

Genetic hearing loss, caused by mutations in critical auditory genes, has seen promising advances through gene therapy, yet the temporal dynamics of early-stage auditory functional recovery and therapeutic transgene expression patterns following intervention remain uncharacterized in preclinical deafness models. This study systematically investigates the post-treatment progression of cochlear functional restoration and spatially resolved transgene expression kinetics in adult knockout ( ) mice following adeno-associated virus (AAV)-mediated inner ear gene therapy. AAV8 vectors delivering were injected via the posterior semicircular canal (PSCC), with auditory brainstem response (ABR) thresholds and cochlear transgene expression assessed at days 1-14 post-injection.

Cochlear transcript diversity and its role in auditory functions implied by an otoferlin short isoform.

Isoforms of a gene may contribute to diverse biological functions. In the cochlea, the repertoire of alternative isoforms remains unexplored. We integrated single-cell short-read and long-read RNA sequencing techniques and identified 236,012 transcripts, 126,612 of which were unannotated in the GENCODE database.

Gene Therapy Restores Auditory Functions in an Adult Vglut3 Knockout Mouse Model.

Adeno-associated virus (AAV)-based gene therapy has been demonstrated to be extremely effective for treating genetic hearing loss over the past several years. However, successful gene therapies for hereditary deafness have not been well-studied in adult mice. To explore the possibility of gene therapy after peripheral auditory maturity, we used AAV8 to express vesicular glutamate transporter 3 (Vglut3) in the cochleae of 5w, 8w, and 20w Vglut3 mice.

AAV-ie-K558R mediated cochlear gene therapy and hair cell regeneration.

The cochlea consists of multiple types of cells, including hair cells, supporting cells and spiral ganglion neurons, and is responsible for converting mechanical forces into electric signals that enable hearing. Genetic and environmental factors can result in dysfunctions of cochlear and auditory systems. In recent years, gene therapy has emerged as a promising treatment in animal deafness models.

Mitochondrial Dysfunction and Therapeutic Targets in Auditory Neuropathy.

Sensorineural hearing loss (SNHL) becomes an inevitable worldwide public health issue, and deafness treatment is urgently imperative; yet their current curative therapy is limited. Auditory neuropathies (AN) were proved to play a substantial role in SNHL recently, and spiral ganglion neuron (SGN) dysfunction is a dominant pathogenesis of AN. Auditory pathway is a high energy consumption system, and SGNs required sufficient mitochondria.

Characterization of promoters for adeno-associated virus mediated efficient Cas9 activation in adult Cas9 knock-in murine cochleae.

CRISPR/Cas9 gene editing enables the treatment of hearing loss in congenitally deaf neonatal mice via both viral and non-viral delivery. While adeno-associated virus (AAV)-mediated gene delivery systems have been shown to be effective tools for gene replacement in the inner ear, application of the AAV-mediated CRISPR/Cas9 gene-editing approach for this purpose is yet to be documented. Based on our previous findings, we focused on the effects of several AAVs delivered via canalostomy injection in adult mice.

Adeno-associated virus vector enables safe and efficient Cas9 activation in neonatal and adult Cas9 knockin murine cochleae.

Adeno-associated virus (AAV)-mediated gene delivery systems have been shown to be effective tools for gene manipulation in the inner ear. For example, hair cells (HCs) and multiple other cell types can be transduced by the local injection of AAVs into the inner ear. However, application of the AAV-mediated CRISPR/Cas9 gene-editing approach to the inner ear in adult mice has not yet been studied.

Gene editing based hearing impairment research and therapeutics.

Hearing impairment affects 1 in 500 newborns worldwide and nearly one out of three people over the age of 65 (WHO, 2019). Hereditary hearing loss is the most common type of congenital deafness; genetic factors also affect deafness susceptibility. Gene therapies may preserve or restore natural sound perception, and have rescued deafness in multiple hereditary murine models.