Efficient viral transduction in mouse inner ear hair cells with utricle injection and AAV9-PHP.B

Lee, John; Nist-Lund, Carl; Solanes, Paola; Goldberg, Hannah; Wu, Jason; Pan, Bifeng; Schneider, Bernard L.; Holt, Jeffrey R.

doi:10.1016/j.heares.2020.107882

Cited by 62 publications

(70 citation statements)

References 22 publications

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“…Finally, viral injection into the neonatal mouse utricle leads to the transduction of almost 100% of both IHCs and OHCs in the cochlea [ 32 ]. By contrast, injections in adult mice result in much lower levels of OHC transduction.…”

Section: Approaches To the Treatment Of Hearing Lossmentioning

confidence: 99%

“…However, the surgical procedure remains challenging. Lee et al recently showed that AAV9-PHP.B-eGFP injection into the neonatal mouse utricle results in the transduction of almost 100% of both IHCs and OHCs in the cochlea and the vestibular end organs with no deleterious effects on hearing and balance [ 32 ]. This vector and the utricle injection approach are, therefore, more suitable for the delivery of transgenes into the cochlea and vestibular organs of mice with hearing and balance defects.…”

Section: Approaches To the Treatment Of Hearing Lossmentioning

confidence: 99%

See 1 more Smart Citation

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges

Delmaghani

El-Amraoui

2020

JCM

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Hearing impairment is the most frequent sensory deficit in humans of all age groups, from children (1/500) to the elderly (more than 50% of the over-75 s). Over 50% of congenital deafness are hereditary in nature. The other major causes of deafness, which also may have genetic predisposition, are aging, acoustic trauma, ototoxic drugs such as aminoglycosides, and noise exposure. Over the last two decades, the study of inherited deafness forms and related animal models has been instrumental in deciphering the molecular, cellular, and physiological mechanisms of disease. However, there is still no curative treatment for sensorineural deafness. Hearing loss is currently palliated by rehabilitation methods: conventional hearing aids, and for more severe forms, cochlear implants. Efforts are continuing to improve these devices to help users to understand speech in noisy environments and to appreciate music. However, neither approach can mediate a full recovery of hearing sensitivity and/or restoration of the native inner ear sensory epithelia. New therapeutic approaches based on gene transfer and gene editing tools are being developed in animal models. In this review, we focus on the successful restoration of auditory and vestibular functions in certain inner ear conditions, paving the way for future clinical applications.

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Section: Approaches To the Treatment Of Hearing Lossmentioning

confidence: 99%

Section: Approaches To the Treatment Of Hearing Lossmentioning

confidence: 99%

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges

Delmaghani

El-Amraoui

2020

JCM

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“…Initial characterization of natural AAV serotypes revealed a relatively low transduction rate of inner ear cell types, and in particular of OHC (Kilpatrick et al , 2011). However, recently developed synthetic AAV capsids seem to have overcome this hurdle; AAV9‐PHP.B has been shown to transduce both inner and outer hair cells at high rates in mice and non‐human primates (Gyorgy et al , 2019; Ivanchenko et al , 2020; Lee et al , 2020).…”

Section: Introductionmentioning

confidence: 99%

Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness

et al. 2020

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Genetic variants account for approximately half the cases of congenital and early‐onset deafness. Methods and technologies for viral delivery of genes into the inner ear have evolved over the past decade to render gene therapy a viable and attractive approach for treatment. Variants in SYNE4, encoding the protein nesprin‐4, a member of the linker of nucleoskeleton and cytoskeleton (LINC), lead to DFNB76 human deafness. Syne4−/− mice have severe‐to‐profound progressive hearing loss and exhibit mislocalization of hair cell nuclei and hair cell degeneration. We used AAV9‐PHP.B, a recently developed synthetic adeno‐associated virus, to deliver the coding sequence of Syne4 into the inner ears of neonatal Syne4−/− mice. Here we report rescue of hair cell morphology and survival, nearly complete recovery of auditory function, and restoration of auditory‐associated behaviors, without observed adverse effects. Uncertainties remain regarding the durability of the treatment and the time window for intervention in humans, but our results suggest that gene therapy has the potential to prevent hearing loss in humans with SYNE4 mutations.

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“…It is feasible to systematically characterize the specificity of different AAVs to transduce the different cell types in the cochlea. An elegant study showed that AAVs specifically transduced different types of retina in both mice and [35][36][37]. They found that AAV-DJ had relatively high efficiency in SCs, surpassing what has been reported previously [35,38].…”

Section: The Challenges In the Cochlea Gene Therapymentioning

confidence: 92%

Recent development of AAV-based gene therapies for inner ear disorders

et al. 2020

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Gene therapy for auditory diseases is gradually maturing. Recent progress in gene therapy treatments for genetic and acquired hearing loss has demonstrated the feasibility in animal models. However, a number of hurdles, such as lack of safe viral vector with high efficiency and specificity, robust deafness large animal models, translating animal studies to clinic etc., still remain to be solved. It is necessary to overcome these challenges in order to effectively recover auditory function in human patients. Here, we review the progress made in our group, especially our efforts to make more effective and cell typespecific viral vectors for targeting cochlea cells.

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Efficient viral transduction in mouse inner ear hair cells with utricle injection and AAV9-PHP.B

Cited by 62 publications

References 22 publications

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges

Inner Ear Gene Therapies Take Off: Current Promises and Future Challenges

Neonatal AAV gene therapy rescues hearing in a mouse model of SYNE4 deafness

Recent development of AAV-based gene therapies for inner ear disorders

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