rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application

Blanc, F.; Mondain, M.; Bemelmans, Alexis-Pierre; Affortit, Corentin; Puel, Jean–Luc; Wang, Jing

doi:10.3390/jcm9020589

Cited by 13 publications

(7 citation statements)

References 122 publications

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“…A major challenge for the delivery of genetic therapeutic materials into the cochlea comes from the inner ear’s anatomical isolation; it is a small, complex structure encased within the densest portion of the temporal bone ( Salt and Hirose, 2018 ). To date, several local routes have been tested to introduce viral vectors into the cochlea (see for review: ( Blanc et al, 2020 )); one of them is by round-window injection ( Chien et al, 2015 ). After opening the middle ear compartment through the round window membrane, the viral vectors are injected directly in the cochlear perilymph.…”

Section: Introductionmentioning

confidence: 99%

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

Blanc

Bemelmans

Affortit

et al. 2022

Front. Cell Dev. Biol.

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Viral-mediated gene augmentation, silencing, or editing offers tremendous promise for the treatment of inherited and acquired deafness. Inner-ear gene therapies often require a safe, clinically useable and effective route of administration to target both ears, while avoiding damage to the delicate structures of the inner ear. Here, we examined the possibility of using a cisterna magna injection as a new cochlear local route for initiating binaural transduction by different serotypes of the adeno-associated virus (AAV2/8, AAV2/9, AAV2/Anc80L65). The results were compared with those following canalostomy injection, one of the existing standard inner ear local delivery routes. Our results demonstrated that a single injection of AAVs enables high-efficiency binaural transduction of almost all inner hair cells with a basal-apical pattern and of large numbers of spiral ganglion neurons of the basal portion of the cochlea, without affecting auditory function and cochlear structures. Taken together, these results reveal the potential for using a cisterna magna injection as a local route for binaural gene therapy applications, but extensive testing will be required before translation beyond mouse models.

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Section: Introductionmentioning

confidence: 99%

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

Blanc

Bemelmans

Affortit

et al. 2022

Front. Cell Dev. Biol.

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“…SNHL can present either congenitally or in adulthood via a spectrum of conditions and diseases that will be discussed in this review. As SNHL tends to be a progressive condition characterized by permanent, irreversible damage to the inner ear hair cells or vestibulocochlear nerve, effective treatment modalities have yet to be developed (Rubel et al, 2013;Blanc et al, 2020;Farooq et al, 2020). Hearing aids in combination with rehabilitation programs can be used to manage the effects of SNHL in adults and children with mild to moderate SNHL (Walling and Dickson, 2012;Butler et al, 2013;Tomblin et al, 2014;Kim et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Genotype-Phenotype Correlation for Predicting Cochlear Implant Outcome: Current Challenges and Opportunities

et al. 2020

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The use and utility of cochlear implantation has rapidly increased in recent years as technological advances in the field have expanded both the efficacy and eligible patient population for implantation. This review aims to serve as a general overview of the most common hearing disorders that have favorable auditory outcomes with cochlear implants (CI). Hearing loss in children caused by congenital cytomegalovirus infection, syndromic conditions including Pendred Syndrome, and non-syndromic genetic conditions such as hearing impairment associated with GJB2 mutations have shown to be successfully managed by CI. Furthermore, cochlear implantation provides the auditory rehabilitation for the most common etiology of hearing loss in adults and age-related hearing loss (ARHL) or presbycusis. However, in some cases, cochlear implantation have been associated with some challenges. Regarding implantation in children, studies have shown that sometimes parents seem to have unrealistic expectations regarding the ability of CI to provide auditory rehabilitation and speech improvement. Given the evidence revealing the beneficial effects of early intervention via CI in individuals with hearing disorders especially hearing loss due to genetic etiology, early auditory and genetic screening efforts may yield better clinical outcomes. There is a need to better understand genotype-phenotype correlations and CI outcome, so that effective genetic counseling and successful treatment strategies can be developed at the appropriate time for hearing impaired individuals.

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“…Despite ongoing exciting advances in applying the translational gene therapy approach to mouse models of human deafness, many challenges lie ahead before this approach can be used to treat inner ear diseases in humans ( 26 ). The preclinical investigations performed so far demonstrate the feasibility and efficacy of gene therapy for restoring hearing and balance in several mouse models of genetic inner ear defects ( 4 – 9 , 27 , 28 ).…”

Section: Discussionmentioning

confidence: 99%

Extended time frame for restoring inner ear function through gene therapy in Usher1G preclinical model

Lahlou,

Calvet,

Simon

et al. 2024

JCI Insight

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Neonatal gene therapy has been shown to prevent inner ear dysfunction in mouse models of Usher syndrome type I (USH1), the most common genetic cause of combined deafness-blindness and vestibular dysfunction. However, hearing onset occurs after birth in mice and in utero in humans, making it questionable how to transpose murine gene therapy outcomes to clinical settings. Here, we sought to extend the therapeutic time window in a mouse model for USH1G to periods corresponding to human neonatal stages, more suitable for intervention in patients. Mice with deletion of Ush1g ( Ush1g –/– ) were subjected to gene therapy after the hearing onset. The rescue of inner ear hair cell structure was evaluated by confocal imaging and electron microscopy. Hearing and vestibular function were assessed by recordings of the auditory brain stem response and vestibulo-ocular reflex and by locomotor tests. Up to P21, gene therapy significantly restored both the hearing and balance deficits in Ush1g –/– mice. However, beyond this age and up to P30, vestibular function was restored but not hearing. Our data show that effective gene therapy is possible in Ush1g –/– mice well beyond neonatal stages, implying that the therapeutic window for USH1G may be wide enough to be transposable to newborn humans.

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rAAV-Mediated Cochlear Gene Therapy: Prospects and Challenges for Clinical Application

Cited by 13 publications

References 122 publications

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

A Single Cisterna Magna Injection of AAV Leads to Binaural Transduction in Mice

Genotype-Phenotype Correlation for Predicting Cochlear Implant Outcome: Current Challenges and Opportunities

Extended time frame for restoring inner ear function through gene therapy in Usher1G preclinical model

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