Early postnatal virus inoculation into the scala media achieved extensive expression of exogenous green fluorescent protein in the inner ear and preserved auditory brainstem response thresholds

Wang, Yunfeng; Sun, Yu; Chang, Qing; Ahmad, Shoeb; Zhou, Baohua; Kim, Yeunjung; Li, Huawei; Lin, Xiaobo

doi:10.1002/jgm.2701

Cited by 43 publications

(37 citation statements)

References 38 publications

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“…Several delivery strategies have been developed that access the cochlear fluids directly from that portion of the cochlear basal turn facing the middle-ear space. These approaches include: (1) a cochleostomy into either scala tympani or scala media1718224142, (2) injection through the round window membrane5172043, (3) or injection onto the surface of the round window, with or without manipulations to increase penetration38444546. The approach to the posterior canal differs in that the access is not through the middle ear22232425.…”

Section: Discussionmentioning

confidence: 99%

“…Although approaches through the middle ear may be practical in human, where the relevant structures are relatively large, the middle and inner ear spaces in mouse are so small, and the inner ear so delicate, that the surgical access to, and/or injection into, the cochlear fluids seems to unavoidably cause cochlear damage2161722, unless injections are made prior to postnatal day 542. Although Kilpatrick et al .…”

Section: Discussionmentioning

confidence: 99%

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Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction

Suzuki

Hashimoto

Xiao

et al. 2017

Sci Rep

142

135

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The use of viral vectors for inner ear gene therapy is receiving increased attention for treatment of genetic hearing disorders. Most animal studies to date have injected viral suspensions into neonatal ears, via the round window membrane. Achieving transduction of hair cells, or sensory neurons, throughout the cochlea has proven difficult, and no studies have been able to efficiently transduce sensory cells in adult ears while maintaining normal cochlear function. Here, we show, for the first time, successful transduction of all inner hair cells and the majority of outer hair cells in an adult cochlea via virus injection into the posterior semicircular canal. We used a “designer” AAV, AAV2/Anc80L65, in which the main capsid proteins approximate the ancestral sequence state of AAV1, 2, 8, and 9. Our injections also transduced ~10% of spiral ganglion cells and a much larger fraction of their satellite cells. In the vestibular sensory epithelia, the virus transduced large numbers of hair cells and virtually all the supporting cells, along with close to half of the vestibular ganglion cells. We conclude that this viral vector and this delivery route hold great promise for gene therapy applications in both cochlear and vestibular sense organs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction

Suzuki

Hashimoto

Xiao

et al. 2017

Sci Rep

142

135

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“…These results are in contrast to virally expressed VGLUT3, which was exclusively in 100% of the inner HCs (Akil et al , ). Considering that other virally expressed exogenous proteins, including GFP (Akil et al , ; Wang et al , ) and connexin26 (Yu et al , ), all showed nonspecific expression, our results suggest that the cellular specificity achieved by VGLUT3 driven by a nonspecific promoter is an exception rather than a common phenomenon. The ectopic Kcnq1 expression demonstrated in this work also gave us an opportunity to investigate possible side effects of such expression outside the targeted cells.…”

Section: Discussionmentioning

confidence: 71%

Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange‐Nielsen deafness syndrome

et al. 2015

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Mutations in the potassium channel subunit KCNQ1 cause the human severe congenital deafness Jervell and Lange-Nielsen (JLN) syndrome. We applied a gene therapy approach in a mouse model of JLN syndrome (Kcnq1−/− mice) to prevent the development of deafness in the adult stage. A modified adeno-associated virus construct carrying a Kcnq1 expression cassette was injected postnatally (P0–P2) into the endolymph, which resulted in Kcnq1 expression in most cochlear marginal cells where native Kcnq1 is exclusively expressed. We also found that extensive ectopic virally mediated Kcnq1 transgene expression did not affect normal cochlear functions. Examination of cochlear morphology showed that the collapse of the Reissner’s membrane and degeneration of hair cells (HCs) and cells in the spiral ganglia were corrected in Kcnq1−/− mice. Electrophysiological tests showed normal endocochlear potential in treated ears. In addition, auditory brainstem responses showed significant hearing preservation in the injected ears, ranging from 20 dB improvement to complete correction of the deafness phenotype. Our results demonstrate the first successful gene therapy treatment for gene defects specifically affecting the function of the stria vascularis, which is a major site affected by genetic mutations in inherited hearing loss.

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“…A number of AAV serotypes and over 100 naturally occurring AAV variants have been isolated from adenovirus stocks or from human/nonhuman primate tissues. They display different cell tropisms (14), but there are some discrepancies in their reported transduction efficiencies and cell tropisms in the inner ear (26)(27)(28)(29). We thus investigated the ability of several AAV vectors to transduce the inner ear hair cells.…”

Section: Viral Cdna Transfer Restores Sans Expression and Targeting Imentioning

confidence: 99%

Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

Emptoz

Michel

Lelli

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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Our understanding of the mechanisms underlying inherited forms of inner ear deficits has considerably improved during the past 20 y, but we are still far from curative treatments. We investigated gene replacement as a strategy for restoring inner ear functions in a mouse model of Usher syndrome type 1G, characterized by congenital profound deafness and balance disorders. These mice lack the scaffold protein sans, which is involved both in the morphogenesis of the stereociliary bundle, the sensory antenna of inner ear hair cells, and in the mechanoelectrical transduction process. We show that a single delivery of the sans cDNA by the adenoassociated virus 8 to the inner ear of newborn mutant mice reestablishes the expression and targeting of the protein to the tips of stereocilia. The therapeutic gene restores the architecture and mechanosensitivity of stereociliary bundles, improves hearing thresholds, and durably rescues these mice from the balance defects. Our results open up new perspectives for efficient gene therapy of cochlear and vestibular disorders by showing that even severe dysmorphogenesis of stereociliary bundles can be corrected.gene | therapy | balance | mouse | Usher

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Early postnatal virus inoculation into the scala media achieved extensive expression of exogenous green fluorescent protein in the inner ear and preserved auditory brainstem response thresholds

Cited by 43 publications

References 38 publications

Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction

Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction

Virally mediated Kcnq1 gene replacement therapy in the immature scala media restores hearing in a mouse model of human Jervell and Lange‐Nielsen deafness syndrome

Local gene therapy durably restores vestibular function in a mouse model of Usher syndrome type 1G

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