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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2018
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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. |
format | Online Article Text |
id | pubmed-5862133 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
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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