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Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy

We assessed the potential of Lmna-mRNA repair by spliceosome-mediated RNA trans-splicing as a therapeutic approach for LMNA-related congenital muscular dystrophy. This gene therapy strategy leads to reduction of mutated transcript expression for the benefit of corresponding wild-type (WT) transcript...

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Detalles Bibliográficos
Autores principales: Azibani, Feriel, Brull, Astrid, Arandel, Ludovic, Beuvin, Maud, Nelson, Isabelle, Jollet, Arnaud, Ziat, Esma, Prudhon, Bernard, Benkhelifa-Ziyyat, Sofia, Bitoun, Marc, Lorain, Stéphanie, Bonne, Gisèle, Bertrand, Anne T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862133/
https://www.ncbi.nlm.nih.gov/pubmed/29499949
http://dx.doi.org/10.1016/j.omtn.2017.12.012
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author Azibani, Feriel
Brull, Astrid
Arandel, Ludovic
Beuvin, Maud
Nelson, Isabelle
Jollet, Arnaud
Ziat, Esma
Prudhon, Bernard
Benkhelifa-Ziyyat, Sofia
Bitoun, Marc
Lorain, Stéphanie
Bonne, Gisèle
Bertrand, Anne T.
author_facet Azibani, Feriel
Brull, Astrid
Arandel, Ludovic
Beuvin, Maud
Nelson, Isabelle
Jollet, Arnaud
Ziat, Esma
Prudhon, Bernard
Benkhelifa-Ziyyat, Sofia
Bitoun, Marc
Lorain, Stéphanie
Bonne, Gisèle
Bertrand, Anne T.
author_sort Azibani, Feriel
collection PubMed
description We assessed the potential of Lmna-mRNA repair by spliceosome-mediated RNA trans-splicing as a therapeutic approach for LMNA-related congenital muscular dystrophy. This gene therapy strategy leads to reduction of mutated transcript expression for the benefit of corresponding wild-type (WT) transcripts. We developed 5′-RNA pre-trans-splicing molecules containing the first five exons of Lmna and targeting intron 5 of Lmna pre-mRNA. Among nine pre-trans-splicing molecules, differing in the targeted sequence in intron 5 and tested in C2C12 myoblasts, three induced trans-splicing events on endogenous Lmna mRNA and confirmed at protein level. Further analyses performed in primary myotubes derived from an LMNA-related congenital muscular dystrophy (L-CMD) mouse model led to a partial rescue of the mutant phenotype. Finally, we tested this approach in vivo using adeno-associated virus (AAV) delivery in newborn mice and showed that trans-splicing events occurred in WT mice 50 days after AAV delivery, although at a low rate. Altogether, while these results provide the first evidence for reprogramming LMNA mRNA in vitro, strategies to improve the rate of trans-splicing events still need to be developed for efficient application of this therapeutic approach in vivo.
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spelling pubmed-58621332018-03-26 Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy Azibani, Feriel Brull, Astrid Arandel, Ludovic Beuvin, Maud Nelson, Isabelle Jollet, Arnaud Ziat, Esma Prudhon, Bernard Benkhelifa-Ziyyat, Sofia Bitoun, Marc Lorain, Stéphanie Bonne, Gisèle Bertrand, Anne T. Mol Ther Nucleic Acids Article We assessed the potential of Lmna-mRNA repair by spliceosome-mediated RNA trans-splicing as a therapeutic approach for LMNA-related congenital muscular dystrophy. This gene therapy strategy leads to reduction of mutated transcript expression for the benefit of corresponding wild-type (WT) transcripts. We developed 5′-RNA pre-trans-splicing molecules containing the first five exons of Lmna and targeting intron 5 of Lmna pre-mRNA. Among nine pre-trans-splicing molecules, differing in the targeted sequence in intron 5 and tested in C2C12 myoblasts, three induced trans-splicing events on endogenous Lmna mRNA and confirmed at protein level. Further analyses performed in primary myotubes derived from an LMNA-related congenital muscular dystrophy (L-CMD) mouse model led to a partial rescue of the mutant phenotype. Finally, we tested this approach in vivo using adeno-associated virus (AAV) delivery in newborn mice and showed that trans-splicing events occurred in WT mice 50 days after AAV delivery, although at a low rate. Altogether, while these results provide the first evidence for reprogramming LMNA mRNA in vitro, strategies to improve the rate of trans-splicing events still need to be developed for efficient application of this therapeutic approach in vivo. American Society of Gene & Cell Therapy 2018-02-01 /pmc/articles/PMC5862133/ /pubmed/29499949 http://dx.doi.org/10.1016/j.omtn.2017.12.012 Text en © 2018 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Azibani, Feriel
Brull, Astrid
Arandel, Ludovic
Beuvin, Maud
Nelson, Isabelle
Jollet, Arnaud
Ziat, Esma
Prudhon, Bernard
Benkhelifa-Ziyyat, Sofia
Bitoun, Marc
Lorain, Stéphanie
Bonne, Gisèle
Bertrand, Anne T.
Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy
title Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy
title_full Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy
title_fullStr Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy
title_full_unstemmed Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy
title_short Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy
title_sort gene therapy via trans-splicing for lmna-related congenital muscular dystrophy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862133/
https://www.ncbi.nlm.nih.gov/pubmed/29499949
http://dx.doi.org/10.1016/j.omtn.2017.12.012
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