Cochlear gene transfer mediated by adeno‐associated virus: Comparison of two surgical approaches

Chien, Wade W.; McDougald, Devin S.; Roy, Soumen; Fitzgerald, Tracy S.; Cunningham, Lisa L.

doi:10.1002/lary.25317

Cited by 67 publications

(61 citation statements)

References 20 publications

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“…Others have injected GFP-expressing AAV vectors into the normal adult ear, as in the present study, to evaluate the effectiveness of different delivery routes or viral serotypes in either mice16172024, rat25 or guinea pig38. Although the most successful of these prior studies reports near 100% transfection of IHCs in the base of the cochlea after round window injection20, most report significantly less than that, e.g.…”

Section: Discussionmentioning

confidence: 86%

“…Although the most successful of these prior studies reports near 100% transfection of IHCs in the base of the cochlea after round window injection20, most report significantly less than that, e.g. ~30%17 and ~80%38, and all report only 0–20% transduction in the cochlear apex172038. Similarly, although four prior studies have looked at virus delivery via a posterior canal route22232425, none convincingly demonstrated a high targeting efficiency for hair cells throughout the cochlear spiral.…”

Section: Discussionmentioning

confidence: 99%

“…AAVs are attractive candidates, because they are not linked with disease, they are minimally immunogenic, and they can achieve efficient and long-lived transgene expression15. In the inner ear, many naturally occurring AAV variants appear to preferentially target hair cells, which also makes them attractive vectors513161718192021. However, to date, no AAV serotype has been shown to target hair cells throughout the entire cochlear spiral in adults.…”

mentioning

confidence: 99%

“…In the adult, the sensory epithelia of the cochlear and vestibular systems are encased in the hardest bone in the body, and, as highly sensitive mechanosensors, can be easily damaged by mechanical manipulations such as drilling or fluid injections. The three commonly used routes for drug/virus delivery into the inner ear are 1) via the round window membrane, at the base of the cochlear spiral, where it faces the middle ear space, 2) via a hole drilled through the cochlear capsule into the cochlear fluid spaces near the round window, or 3) through a hole drilled into the posterior semicircular canal where it runs near the external surface of the skull1617182022232425. In our experience in animal models, injection through the semicircular canals is the least traumatic to the cochlea.…”

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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

138

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: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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

138

135

View full text Add to dashboard Cite

show abstract

“…The perilymph-filled spaces surrounding the cochlear duct, scala tympani and scala vestibuli can be accessed from the middle ear, either through the oval window membrane or the round window membrane (RWM). The RWM, which is the only non-bony opening into the inner ear, is relatively easily accessible in many animal models, and administration of viral vector using this route has been well tolerated 10, 11, 22 . In humans, cochlear implant placement routinely relies on surgical electrode insertion through the RWM 23 .…”

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confidence: 99%

A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear

et al. 2017

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Efforts to develop gene therapies for hearing loss have been hampered by the lack of safe, efficient, and clinically relevant delivery modalities1, 2. Here we demonstrate the safety and efficiency of Anc80L65, a rationally designed synthetic vector3, for transgene delivery to the mouse cochlea. Cochlear explants incubated with Anc80L65 encoding eGFP demonstrated high level transduction of inner and outer hair cells (60–100%). Injection of Anc80L65 through the round window membrane resulted in highly efficient transduction of inner and outer hair cells, a substantial improvement over conventional adeno-associated virus (AAV) vectors. Anc80L65 round window injection was well tolerated, as indicated by sensory cell function, hearing and vestibular function, and immunologic parameters. The ability of Anc80L65 to target outer hair cells at high rates, a requirement for restoration of complex auditory function, may enable future gene therapies for hearing and balance disorders.

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Emerging Gene Therapies for Genetic Hearing Loss

Ahmed

Shubina-Oleinik

Holt

2017

JARO

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Gene therapy, or the treatment of human disease using genetic material, for inner ear dysfunction is coming of age. Recent progress in developing gene therapy treatments for genetic hearing loss has demonstrated tantalizing proof-of-principle in animal models. While successful translation of this progress into treatments for humans awaits, there is growing interest from patients, scientists, clinicians, and industry. Nonetheless, it is clear that a number of hurdles remain, and expectations for total restoration of auditory function should remain tempered until these challenges have been overcome. Here, we review progress, prospects, and challenges for gene therapy in the inner ear. We focus on technical aspects, including routes of gene delivery to the inner ear, choice of vectors, promoters, inner ear targets, therapeutic strategies, preliminary success stories, and points to consider for translating of these successes to the clinic.

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Cochlear gene transfer mediated by adeno‐associated virus: Comparison of two surgical approaches

Abstract: NA.

Cited by 67 publications

References 20 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

A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear

Emerging Gene Therapies for Genetic Hearing Loss

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