Gene Therapy to the Retina and the Cochlea

Crane, Ryan; Conley, Shannon M.; Al‐Ubaidi, Muayyad R.; Naash, Muna I.

doi:10.3389/fnins.2021.652215

Cited by 14 publications

(12 citation statements)

References 216 publications

(258 reference statements)

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“…These findings will greatly facilitate the accurate delivery of novel therapeutic agents to their target structures in the inner ear and will thus derisk future clinical trials. The application of SR-PCI to the auditory system also dovetails with an escalation of interest in regenerative inner ear therapies which hold considerable promise for addressing the growing health burden of hearing loss [14][15][16] . While considerable challenges remain in developing novel therapeutics for use in humans 17 , we believe that these developments herald a new era for the application of regenerative therapeutics to the inner ear.…”

Section: Discussionmentioning

confidence: 99%

Unlocking the human inner ear for therapeutic intervention

Agrawal

Rohani

et al. 2022

Sci Rep

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The human inner ear contains minute three-dimensional neurosensory structures that are deeply embedded within the skull base, rendering them relatively inaccessible to regenerative therapies for hearing loss. Here we provide a detailed characterisation of the functional architecture of the space that hosts the cell bodies of the auditory nerve to make them safely accessible for the first time for therapeutic intervention. We used synchrotron phase-contrast imaging which offers the required microscopic soft-tissue contrast definition while simultaneously displaying precise bony anatomic detail. Using volume-rendering software we constructed highly accurate 3-dimensional representations of the inner ear. The cell bodies are arranged in a bony helical canal that spirals from the base of the cochlea to its apex; the canal volume is 1.6 μL but with a diffusion potential of 15 μL. Modelling data from 10 temporal bones enabled definition of a safe trajectory for therapeutic access while preserving the cochlea’s internal architecture. We validated the approach through surgical simulation, anatomical dissection and micro-radiographic analysis. These findings will facilitate future clinical trials of novel therapeutic interventions to restore hearing.

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Section: Discussionmentioning

confidence: 99%

Unlocking the human inner ear for therapeutic intervention

Agrawal

Rohani

et al. 2022

Sci Rep

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“…Vision and/or hearing impairments are the most common forms of sensory disorders in humans (Géléoc and El-Amraoui, 2020;Crane et al, 2021). Multiple causes can lead to sensory deficits, including genetic, environmental (including infections, oto-or photo-toxic drugs, noise or light exposure), or aging.…”

Section: Inherited Retinal Dystrophies and Deafnessmentioning

confidence: 99%

“…This pioneering work led to the historical approval of the first gene therapy product, Luxturna, by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) to treat Leber congenital amaurosis. This groundbreaking advancement of RPE65 gene therapy paved the way for numerous breakthrough clinical phase I/II trials exploring gene replacement for monogenic recessive diseases of the retina, such as choroideremia, retinoschisis, achromatopsia, Usher syndrome, and Leber hereditary optic neuropathy (Buck and Wijnholds, 2020;Botto et al, 2021;Crane et al, 2021). Thanks to new generation of viral vectors, successful gene replacement strategies targeting key deafness genes have been established, using single or double AAV vector-mediated delivery (see Sacheli et al, 2013;Askew and Chien, 2020;Géléoc and El-Amraoui, 2020).…”

Section: Gene Therapy For Inherited Retinal Dystrophies and Auditory Deficitsmentioning

confidence: 99%

“…Any impairment of these senses has a profound negative impact on the quality of life of the affected individuals, restricting their communication and reducing access to social activities, entertainment and working opportunities. In turn, this can lead to social isolation and depression (Delmaghani and El-Amraoui, 2020;Géléoc and El-Amraoui, 2020;Crane et al, 2021). Based on comprehensive empirical data, the World Health Organization has estimated that about 285 million people worldwide currently suffer from severe visual impairment (see http://www.who.int/).…”

Section: Introductionmentioning

confidence: 99%

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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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“…As a result, in the past decades much effort has been focused on the development of novel delivery methods for targeted therapeutic delivery to the outer retina. Nanoscale delivery of genetic therapies to ameliorate phenotypes associated with IRD has taken many forms, including gene supplementation, knockdown, and most recently, delivery of CRISPR based approaches for gene editing (recently reviewed in [ 2 ]). While all of these approaches have been successfully employed in animal models, only one retinal gene therapy has thus far been FDA-approved for use in humans, an adeno-associated virus (AAV) carrying RPE65, which is subretinally delivered to patients with Leber’s congenital amaurosis (first described in [ 3 , 4 , 5 ]).…”

Section: Introductionmentioning

confidence: 99%

Co-Injection of Sulfotyrosine Facilitates Retinal Uptake of Hyaluronic Acid Nanospheres Following Intravitreal Injection

et al. 2021

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Gene and drug delivery to the retina is a critical therapeutic goal. While the majority of inherited forms of retinal degeneration affect the outer retina, specifically the photoreceptors and retinal pigment epithelium, effective targeted delivery to this region requires invasive subretinal delivery. Our goal in this work was to evaluate two innovative approaches for increasing both the persistence of delivered nanospheres and their penetration into the outer retina while using the much less invasive intravitreal delivery method. We formulated novel hyaluronic acid nanospheres (HA-NS, 250 nm and 500 nm in diameter) conjugated to fluorescent reporters and delivered them intravitreally to the adult Balb/C mouse retina. They exhibited persistence in the vitreous and along the inner limiting membrane (ILM) for up to 30 days (longest timepoint examined) but little retinal penetration. We thus evaluated the ability of the small molecule, sulfotyrosine, to disrupt the ILM, and found that 3.2 µg/µL sulfotyrosine led to significant improvement in delivery to the outer retina following intravitreal injections without causing retinal inflammation, degeneration, or loss of function. Co-delivery of sulfotyrosine and HA-NS led to robust improvements in penetration of HA-NS into the retina and accumulation along the interface between the photoreceptors and the retinal pigment epithelium. These exciting findings suggest that sulfotyrosine and HA-NS may be an effective strategy for outer retinal targeting after intravitreal injection.

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Gene Therapy to the Retina and the Cochlea

Cited by 14 publications

References 216 publications

Unlocking the human inner ear for therapeutic intervention

Unlocking the human inner ear for therapeutic intervention

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

Co-Injection of Sulfotyrosine Facilitates Retinal Uptake of Hyaluronic Acid Nanospheres Following Intravitreal Injection

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