title: mRNA trans-splicing in gene therapy for genetic diseases.
abstract: Spliceosome-mediated RNA trans-splicing, or SMaRT, is a promising strategy to design innovative gene therapy solutions for currently intractable genetic diseases. SMaRT relies on the correction of mutations at the post-transcriptional level by modifying the mRNA sequence. To achieve this, an exogenous RNA is introduced into the target cell, usually by means of gene transfer, to induce a splice event in trans between the exogenous RNA and the target endogenous pre-mRNA. This produces a chimeric mRNA composed partly of exons of the latter, and partly of exons of the former, encoding a sequence free of mutations. The principal challenge of SMaRT technology is to achieve a reaction as complete as possible, i.e., resulting in 100% repairing of the endogenous mRNA target. The proof of concept of SMaRT feasibility has already been established in several models of genetic diseases caused by recessive mutations. In such cases, in fact, the repair of only a portion of the mutant mRNA pool may be sufficient to obtain a significant therapeutic effect. However in the case of dominant mutations, the target cell must be freed from the majority of mutant mRNA copies, requiring a highly efficient trans-splicing reaction. This likely explains why only a few examples of SMaRT approaches targeting dominant mutations are reported in the literature. In this review, we explain in details the mechanism of trans-splicing, review the different strategies that are under evaluation to lead to efficient trans-splicing, and discuss the advantages and limitations of SMaRT. WIREs RNA 2016, 7:487-498. doi: 10.1002/wrna.1347 For further resources related to this article, please visit the WIREs website.
authors.affiliation: Centre de recherche Institut de la Vision, Sorbonne Universités, Université Pierre et Marie Curie UM80, Paris, France.
authors.forename: Adeline
authors.initials: A
authors.lastname: Berger
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France.|Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, Fontenay-aux-Roses, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Maire
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France.|Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, Fontenay-aux-Roses, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gaillard
authors.affiliation: Centre de recherche Institut de la Vision, Sorbonne Universités, Université Pierre et Marie Curie UM80, Paris, France.|Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, INSERM-DHOS, Paris, France.|Fondation Ophtalmologique Adolphe de Rothschild, Paris, France.|Institute of Ophthalmology, University College of London, London, UK.
authors.forename: José-Alain
authors.initials: JA
authors.lastname: Sahel
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France.|Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, Fontenay-aux-Roses, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Hantraye
authors.affiliation: Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Département des Sciences du Vivant (DSV), Institut d'Imagerie Biomédicale (I2BM), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France.|Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud, Université Paris-Saclay, UMR 9199, Neurodegenerative Diseases Laboratory, Fontenay-aux-Roses, France.
authors.forename: Alexis-Pierre
authors.initials: AP
authors.lastname: Bemelmans
mesh_terms: D000818:Animals; D030342:Genetic Diseases, Inborn / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism*; D020040:Trans-Splicing
chemical_list: D012333:RNA, Messenger