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mRNA trans‐splicing in gene therapy for genetic diseases

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 exogeno...

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Autores principales: Berger, Adeline, Maire, Séverine, Gaillard, Marie‐Claude, Sahel, José‐Alain, Hantraye, Philippe, Bemelmans, Alexis‐Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071737/
https://www.ncbi.nlm.nih.gov/pubmed/27018401
http://dx.doi.org/10.1002/wrna.1347
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author Berger, Adeline
Maire, Séverine
Gaillard, Marie‐Claude
Sahel, José‐Alain
Hantraye, Philippe
Bemelmans, Alexis‐Pierre
author_facet Berger, Adeline
Maire, Séverine
Gaillard, Marie‐Claude
Sahel, José‐Alain
Hantraye, Philippe
Bemelmans, Alexis‐Pierre
author_sort Berger, Adeline
collection PubMed
description 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.
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spelling pubmed-50717372016-11-02 mRNA trans‐splicing in gene therapy for genetic diseases Berger, Adeline Maire, Séverine Gaillard, Marie‐Claude Sahel, José‐Alain Hantraye, Philippe Bemelmans, Alexis‐Pierre Wiley Interdiscip Rev RNA Advanced Reviews 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. John Wiley & Sons, Inc. 2016-03-28 2016 /pmc/articles/PMC5071737/ /pubmed/27018401 http://dx.doi.org/10.1002/wrna.1347 Text en © 2016 The Authors. WIREs RNA published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Advanced Reviews
Berger, Adeline
Maire, Séverine
Gaillard, Marie‐Claude
Sahel, José‐Alain
Hantraye, Philippe
Bemelmans, Alexis‐Pierre
mRNA trans‐splicing in gene therapy for genetic diseases
title mRNA trans‐splicing in gene therapy for genetic diseases
title_full mRNA trans‐splicing in gene therapy for genetic diseases
title_fullStr mRNA trans‐splicing in gene therapy for genetic diseases
title_full_unstemmed mRNA trans‐splicing in gene therapy for genetic diseases
title_short mRNA trans‐splicing in gene therapy for genetic diseases
title_sort mrna trans‐splicing in gene therapy for genetic diseases
topic Advanced Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071737/
https://www.ncbi.nlm.nih.gov/pubmed/27018401
http://dx.doi.org/10.1002/wrna.1347
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