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      Genome Editing as a Treatment for the Most Prevalent Causative Genes of Autosomal Dominant Retinitis Pigmentosa

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          Abstract

          Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of diseases with more than 250 causative genes. The most common form is retinitis pigmentosa. IRDs lead to vision impairment for which there is no universal cure. Encouragingly, a first gene supplementation therapy has been approved for an autosomal recessive IRD. However, for autosomal dominant IRDs, gene supplementation therapy is not always pertinent because haploinsufficiency is not the only cause. Disease-causing mechanisms are often gain-of-function or dominant-negative, which usually require alternative therapeutic approaches. In such cases, genome-editing technology has raised hopes for treatment. Genome editing could be used to (i) invalidate both alleles, followed by supplementation of the wild type gene, (ii) specifically invalidate the mutant allele, with or without gene supplementation, or (iii) to correct the mutant allele. We review here the most prevalent genes causing autosomal dominant retinitis pigmentosa and the most appropriate genome-editing strategy that could be used to target their different causative mutations.

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          Most cited references106

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          Targeting DNA double-strand breaks with TAL effector nucleases.

          Engineered nucleases that cleave specific DNA sequences in vivo are valuable reagents for targeted mutagenesis. Here we report a new class of sequence-specific nucleases created by fusing transcription activator-like effectors (TALEs) to the catalytic domain of the FokI endonuclease. Both native and custom TALE-nuclease fusions direct DNA double-strand breaks to specific, targeted sites.
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            CRISPR/Cas9 in Genome Editing and Beyond

            The Cas9 protein (CRISPR-associated protein 9), derived from type II CRISPR (clustered regularly interspaced short palindromic repeats) bacterial immune systems, is emerging as a powerful tool for engineering the genome in diverse organisms. As an RNA-guided DNA endonuclease, Cas9 can be easily programmed to target new sites by altering its guide RNA sequence, and its development as a tool has made sequence-specific gene editing several magnitudes easier. The nuclease-deactivated form of Cas9 further provides a versatile RNA-guided DNA-targeting platform for regulating and imaging the genome, as well as for rewriting the epigenetic status, all in a sequence-specific manner. With all of these advances, we have just begun to explore the possible applications of Cas9 in biomedical research and therapeutics. In this review, we describe the current models of Cas9 function and the structural and biochemical studies that support it. We focus on the applications of Cas9 for genome editing, regulation, and imaging, discuss other possible applications and some technical considerations, and highlight the many advantages that CRISPR/Cas9 technology offers.
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              Increasing the genome-targeting scope and precision of base editing with engineered Cas9-cytidine deaminase fusions

              Base editing is a recently developed approach to genome editing that uses a fusion protein containing a catalytically defective Streptococcus pyogenes Cas9, a cytidine deaminase, and an inhibitor of base excision repair to induce programmable, single-nucleotide changes in the DNA of living cells without generating double-strand DNA breaks, without requiring a donor DNA template, and without inducing an excess of stochastic insertions and deletions 1 . Here we report the development of five new C→T (or G→A) base editors that use natural and engineered Cas9 variants with different protospacer-adjacent motif (PAM) specificities to expand the number of sites that can be targeted by base editing by 2.5-fold. Additionally, we engineered new base editors containing mutated cytidine deaminase domains that narrow the width of the apparent editing window from approximately 5 nucleotides to as little as 1 to 2 nucleotides, enabling the discrimination of neighboring C nucleotides that would previously be edited with comparable efficiency, thereby doubling the number of disease-associated target Cs that can be corrected preferentially over nearby non-target Cs. Collectively, these developments substantially increase the targeting scope of base editing and establish the modular nature of base editors.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                23 May 2019
                May 2019
                : 20
                : 10
                : 2542
                Affiliations
                [1 ]Inserm U1051, Institute for Neurosciences of Montpellier, 80 Avenue Augustin Fliche, 34091 Montpellier, France; michalitsa.diakatou@ 123456inserm.fr (M.D.); gael.manes@ 123456inserm.fr (G.M.); beatrice.bocquet@ 123456inserm.fr (B.B.); isabelannemeunier@ 123456yahoo.fr (I.M.)
                [2 ]University of Montpellier, 34095 Montpellier, France
                [3 ]National Reference Centre for Inherited Sensory Diseases, CHU, 34295 Montpellier, France
                Author notes
                [* ]Correspondence: vasiliki.kalatzis@ 123456inserm.fr ; Tel.: +33-(0)4-9963-6076; Fax: +33-(0)4-9963-6020
                Author information
                https://orcid.org/0000-0003-1871-0636
                Article
                ijms-20-02542
                10.3390/ijms20102542
                6567127
                31126147
                7b77e83d-1039-4949-bd4f-acf0f78e3b29
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 25 April 2019
                : 22 May 2019
                Categories
                Review

                Molecular biology
                inherited retinal dystrophies,autosomal dominant retinitis pigmentosa,photoreceptors,loss-of-function,gain-of-function,dominant-negative,crispr/cas,gene supplementation,genome-editing,aav vector

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