Gene Editing Preserves Visual Functions in a Mouse Model of Retinal Degeneration

Vagni, Paola; Perlini, Laura E.; Chenais, Naïg Aurélia Lüdmilla; Marchetti, Tommaso; Parrini, Martina; Contestabile, Andrea; Cancedda, Laura; Ghezzi, Diego

doi:10.3389/fnins.2019.00945

Cited by 28 publications

(25 citation statements)

References 73 publications

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“…When dCas9-VPR/Opn1mw-gRNA under the control of the rhodopsin promoter was delivered to the Rho ± retina, researchers observed expression of M-opsin in rods, and importantly, improvements in scotopic vision and retinal structure. Genome editing in the mouse retina has also been attempted for Pde6b-associated RP (using electroporation), Cep290-associated LCA (further discussed below), and Gucy2d-associated cone-rod dystrophy (Ruan et al, 2017;McCullough et al, 2019;Vagni et al, 2019). Somatic genome-editing, and non-genome editing CRISPR-based therapeutic strategies are likely to become increasingly prevalent, particularly as tools to block chronic Cas9 activity, suppress immune responses, and increase the efficiency of homology directed repair are developed (reviewed in Nakamura et al, 2021).…”

Section: Gene Therapy In the Retina And Cochlea Preclinical Gene Therapy In The Retinamentioning

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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Section: Gene Therapy In the Retina And Cochlea Preclinical Gene Therapy In The Retinamentioning

confidence: 99%

Gene Therapy to the Retina and the Cochlea

et al. 2021

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“…To date, neither the PE nor the BE approach has been used to correct the rd10 model. However, Vagni and others illustrated the amenability of the rd10 model to in vivo treatment using CRISPR/Cas9-mediated HDR ( Vagni et al, 2019 ). Their findings revealed a higher visual acuity compared to the untreated eye 3 months post gene editing ( Vagni et al, 2019 ).…”

Section: Crispr-based Gene Editing: a Brief Overviewmentioning

confidence: 99%

Prime Editing for Inherited Retinal Diseases

et al. 2021

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Inherited retinal diseases (IRDs) are chronic, hereditary disorders that lead to progressive degeneration of the retina. Disease etiology originates from a genetic mutation—inherited or de novo—with a majority of IRDs resulting from point mutations. Given the plethora of IRDs, to date, mutations that cause these dystrophies have been found in approximately 280 genes. However, there is currently only one FDA-approved gene augmentation therapy, Luxturna (voretigene neparvovec-rzyl), available to patients with RPE65-mediated retinitis pigmentosa (RP). Although clinical trials for other genes are underway, these techniques typically involve gene augmentation rather than genome surgery. While gene augmentation therapy delivers a healthy copy of DNA to the cells of the retina, genome surgery uses clustered regularly interspaced short palindromic repeats (CRISPR)-based technology to correct a specific genetic mutation within the endogenous genome sequence. A new technique known as prime editing (PE) applies a CRISPR-based technology that possesses the potential to correct all twelve possible transition and transversion mutations as well as small insertions and deletions. EDIT-101, a CRISPR-based therapy that is currently in clinical trials, uses double-strand breaks and nonhomologous end joining to remove the IVS26 mutation in the CEP290 gene. Preferably, PE does not cause double-strand breaks nor does it require any donor DNA repair template, highlighting its unparalleled efficiency. Instead, PE uses reverse transcriptase and Cas9 nickase to repair mutations in the genome. While this technique is still developing, with several challenges yet to be addressed, it offers promising implications for the future of IRD treatment.

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“…A similar strategy is applied when the main goal is to study the validity of the CRISPR system for gene editing in a mouse model. As a first step, usually, researchers test the designed RNA guides in manageable culture cells of mouse origin, such as the Mouse Neuro 2A (N2A) cells, derived from a mouse neuroblastoma, or mouse embryonic fibroblasts [40,41].…”

Section: Cell Linesmentioning

confidence: 99%

Application of CRISPR Tools for Variant Interpretation and Disease Modeling in Inherited Retinal Dystrophies

Fuster-García

García‐Bohórquez

Rodríguez-Muñoz

et al. 2020

Genes

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Inherited retinal dystrophies are an assorted group of rare diseases that collectively account for the major cause of visual impairment of genetic origin worldwide. Besides clinically, these vision loss disorders present a high genetic and allelic heterogeneity. To date, over 250 genes have been associated to retinal dystrophies with reported causative variants of every nature (nonsense, missense, frameshift, splice-site, large rearrangements, and so forth). Except for a fistful of mutations, most of them are private and affect one or few families, making it a challenge to ratify the newly identified candidate genes or the pathogenicity of dubious variants in disease-associated loci. A recurrent option involves altering the gene in in vitro or in vivo systems to contrast the resulting phenotype and molecular imprint. To validate specific mutations, the process must rely on simulating the precise genetic change, which, until recently, proved to be a difficult endeavor. The rise of the CRISPR/Cas9 technology and its adaptation for genetic engineering now offers a resourceful suite of tools to alleviate the process of functional studies. Here we review the implementation of these RNA-programmable Cas9 nucleases in culture-based and animal models to elucidate the role of novel genes and variants in retinal dystrophies.

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Gene Editing Preserves Visual Functions in a Mouse Model of Retinal Degeneration

Cited by 28 publications

References 73 publications

Gene Therapy to the Retina and the Cochlea

Gene Therapy to the Retina and the Cochlea

Prime Editing for Inherited Retinal Diseases

Application of CRISPR Tools for Variant Interpretation and Disease Modeling in Inherited Retinal Dystrophies

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