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

Lan, Yiyang; Tao, Yong; Wang, Yunfeng; Ke, Junzi; Yang, Qiuxiang; Liu, Xiaoyi; Su, Bing; Wu, Yi-Chien; Lin, Chao-Po; Zhong, Guisheng

doi:10.1038/s41434-020-0155-7

Cited by 12 publications

(11 citation statements)

References 97 publications

(133 reference statements)

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“…Inflammatory responses in the brain or ears remain a concern for the development of future inner ear therapeutics, whether through direct inner ear injections or cisterna magna injections, although our work found no evidence in the latter case ( 17 , 50 ). Emerging studies suggest that the appropriate capsids and promoters may optimize the therapeutic specificity while minimizing the risks and side effects of viral treatment ( 2 , 51 ). Thus, the successful delivery of viral gene therapy to treat hearing loss in the adult cochlea via CSF has promising translational implications.…”

Section: Discussionmentioning

confidence: 99%

Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice

et al. 2023

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Inner ear gene therapy has recently effectively restored hearing in neonatal mice, but it is complicated in adulthood by the structural inaccessibility of the cochlea, which is embedded within the temporal bone. Alternative delivery routes may advance auditory research and also prove useful when translated to humans with progressive genetic-mediated hearing loss. Cerebrospinal fluid flow via the glymphatic system is emerging as a new approach for brain-wide drug delivery in rodents as well as humans. The cerebrospinal fluid and the fluid of the inner ear are connected via a bony channel called the cochlear aqueduct, but previous studies have not explored the possibility of delivering gene therapy via the cerebrospinal fluid to restore hearing in adult deaf mice. Here, we showed that the cochlear aqueduct in mice exhibits lymphatic-like characteristics. In vivo time-lapse magnetic resonance imaging, computed tomography, and optical fluorescence microscopy showed that large-particle tracers injected into the cerebrospinal fluid reached the inner ear by dispersive transport via the cochlear aqueduct in adult mice. A single intracisternal injection of adeno-associated virus carrying solute carrier family 17, member 8 ( Slc17A8 ), which encodes vesicular glutamate transporter-3 (VGLUT3), rescued hearing in adult deaf Slc17A8 −/− mice by restoring VGLUT3 protein expression in inner hair cells, with minimal ectopic expression in the brain and none in the liver. Our findings demonstrate that cerebrospinal fluid transport comprises an accessible route for gene delivery to the adult inner ear and may represent an important step toward using gene therapy to restore hearing in humans.

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Section: Discussionmentioning

confidence: 99%

Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice

et al. 2023

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“…As mentioned above, AAV vectors are currently the leading choice for in vivo gene transfer studies, with over 40 gene therapy clinical trials, thanks to their non-pathogenicity, low immunogenicity and their ability to mediate persistent transgene expression. Numerous AAV serotypes and variants have been tested using different injection routes into the eye and the inner ear, documenting their safety and efficiency to target specific retinal or inner ear cell types (Buck and Wijnholds, 2020;Fakhiri et al, 2020;Lan et al, 2020). The capsid serotype and promoter in front of the transgene are key parameters determining expression in a given cell type.…”

Section: The Improvement Of Delivery Technologies Drives Major Advances In Eye and Inner Ear Therapeuticsmentioning

confidence: 99%

Progress in Gene Editing Tools and Their Potential for Correcting Mutations Underlying Hearing and Vision Loss

Botto

Dalkara²,

El-Amraoui³

2021

Front. Genome Ed.

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Blindness and deafness are the most frequent sensory disorders in humans. Whatever their cause — genetic, environmental, or due to toxic agents, or aging — the deterioration of these senses is often linked to irreversible damage to the light-sensing photoreceptor cells (blindness) and/or the mechanosensitive hair cells (deafness). Efforts are increasingly focused on preventing disease progression by correcting or replacing the blindness and deafness-causal pathogenic alleles. In recent years, gene replacement therapies for rare monogenic disorders of the retina have given positive results, leading to the marketing of the first gene therapy product for a form of childhood hereditary blindness. Promising results, with a partial restoration of auditory function, have also been reported in preclinical models of human deafness. Silencing approaches, including antisense oligonucleotides, adeno-associated virus (AAV)–mediated microRNA delivery, and genome-editing approaches have also been applied to various genetic forms of blindness and deafness The discovery of new DNA- and RNA-based CRISPR/Cas nucleases, and the new generations of base, prime, and RNA editors offers new possibilities for directly repairing point mutations and therapeutically restoring gene function. Thanks to easy access and immune-privilege status of self-contained compartments, the eye and the ear continue to be at the forefront of developing therapies for genetic diseases. Here, we review the ongoing applications and achievements of this new class of emerging therapeutics in the sensory organs of vision and hearing, highlighting the challenges ahead and the solutions to be overcome for their successful therapeutic application in vivo.

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“…Subsequently, antisense oligonucleotides were used to correct splicing in an Usher syndrome mouse model ( Ush1c ) leading to functional improvements in low-frequency hearing ( Lentz et al, 2013 ; Ponnath et al, 2018 ; Wang et al, 2020 ). Since then, some AAV-mediated functional and/or structural rescue has been reported in multiple inherited models of deafness, including those associated with mutations in the gap junction gene connexin 26, the potassium channel subunit Kcnq1 , the stereocilia gene whirlin, the antioxidant gene Msr3b , the usher 1C gene harmonin, the usher 3 gene clarin, the gene Slc26a4 , and the ion channel Tmc1 , among others ( Yu et al, 2014 ; Chang et al, 2015 ; Iizuka et al, 2015 ; Chien et al, 2016 ; Kim et al, 2016 ; Pan et al, 2017 ; Dulon et al, 2018 ; Nist-Lund et al, 2019 ; Lan et al, 2020 ; Figure 1D ).…”

Section: Gene Therapy In the Retina And Cochleamentioning

confidence: 99%

Gene Therapy to the Retina and the Cochlea

et al. 2021

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Vision and hearing disorders comprise the most common sensory disorders found in people. Many forms of vision and hearing loss are inherited and current treatments only provide patients with temporary or partial relief. As a result, developing genetic therapies for any of the several hundred known causative genes underlying inherited retinal and cochlear disorders has been of great interest. Recent exciting advances in gene therapy have shown promise for the clinical treatment of inherited retinal diseases, and while clinical gene therapies for cochlear disease are not yet available, research in the last several years has resulted in significant advancement in preclinical development for gene delivery to the cochlea. Furthermore, the development of somatic targeted genome editing using CRISPR/Cas9 has brought new possibilities for the treatment of dominant or gain-of-function disease. Here we discuss the current state of gene therapy for inherited diseases of the retina and cochlea with an eye toward areas that still need additional development.

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

Cited by 12 publications

References 97 publications

Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice

Delivery of gene therapy through a cerebrospinal fluid conduit to rescue hearing in adult mice

Progress in Gene Editing Tools and Their Potential for Correcting Mutations Underlying Hearing and Vision Loss

Gene Therapy to the Retina and the Cochlea

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