Journal ArticleDOI
Meganucleases and DNA double-strand break-induced recombination : Perspectives for gene therapy
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TLDR
Current systems based on redesigned endonucleases will be presented, with a special emphasis on the recent advances in homing endonuclease engineering, and the main issues that will need to be addressed in order to bring this promising technology to the patient.Abstract:
Meganucleases are sequence-specific endonucleases recognizing large (>12 bp) sequence sites and several laboratories have used these proteins to induce highly efficient gene targeting in mammalian cells. The recent development of artificial endonucleases with tailored specificities has opened the door for a wide range of new applications, including therapeutic ones: redesigned endonucleases cleaving chosen sequences could be used to in gene therapy to correct mutated genes or introduce transgenes in chosen loci. Such "targeted" approaches markedly differ from current gene therapy strategies based on the random insertion of a complementing virus-borne transgene. As a consequence, they should bypass the odds of random insertion. Artificial fusion proteins including Zinc-Finger binding domains have provided important proofs of concept, however the toxicity of these proteins is still an issue. Today custom-designed homing endonucleases, the natural meganucleases, could represent an efficient alternative. After a brief description of the origin of the technology, current systems based on redesigned endonucleases will be presented, with a special emphasis on the recent advances in homing endonuclease engineering. Finally, we will discuss the main issues that will need to be addressed in order to bring this promising technology to the patient.read more
Citations
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Journal ArticleDOI
Genetic Therapeutic Approaches for Duchenne Muscular Dystrophy
TL;DR: Genetic-based therapeutic strategies aimed at the amelioration of the DMD phenotype are discussed, in terms of the more recent advances, and the hurdles to be overcome if a comprehensive and effective treatment for DMD is to be found.
Journal ArticleDOI
Ex Vivo COL7A1 Correction for Recessive Dystrophic Epidermolysis Bullosa Using CRISPR/Cas9 and Homology-Directed Repair
Araksya Izmiryan,Clarisse Ganier,Clarisse Ganier,Matteo Bovolenta,Alain Schmitt,Fulvio Mavilio,Alain Hovnanian,Alain Hovnanian +7 more
TL;DR: Grafting of genetically corrected 3D skin equivalents onto nude mice showed up to 26% re-expression and normal localization of type VII collagen as well as anchoring fibril formation at the dermal-epidermal junction, providing evidence that precise genome editing in primary RDEB cells is a relevant strategy to genetically correct COL7A1 mutations for the development of future ex vivo clinical applications.
Journal ArticleDOI
Gene targeting and editing in crop plants: a new era of precision opportunities
Amy Rinaldo,Michael Ayliffe +1 more
TL;DR: The basis of each designer nuclease platform is described, highlighting the advantages and disadvantages of each, and examples of their application in crop improvement are given.
Journal ArticleDOI
Chemical Biology Approaches to Genome Editing: Understanding, Controlling, and Delivering Programmable Nucleases
TL;DR: Advancing the capabilities, safety, effectiveness, and therapeutic relevance of genome-engineering proteins will continue to rely on chemical biology strategies that manipulate their activity, specificity, and localization.
Journal ArticleDOI
ATM Limits Incorrect End Utilization during Non-Homologous End Joining of Multiple Chromosome Breaks
Nicole Bennardo,Jeremy M. Stark +1 more
TL;DR: It is suggested that ATM is important to limit incorrect end utilization during c-NHEJ, to limit the increase in Distal-EJ caused by ATM disruption and classical non-homologous end joining factors, specifically DNA-PKcs, Xrcc4, and XLF.
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Journal ArticleDOI
The double-strand-break repair model for recombination
TL;DR: This work proposes a new mechanism for meiotic recombination, in which events are initiated by double-strand breaks that are enlarged to double- Strand gaps, and postmeiotic segregation can result from heteroduplex DNA formed at the boundaries of the gap-repair region.