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

Autor:	Azibani F; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Brull A; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Arandel L; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Beuvin M; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Nelson I; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Jollet A; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Ziat E; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Prudhon B; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Benkhelifa-Ziyyat S; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Bitoun M; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Lorain S; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Bonne G; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France., Bertrand AT; Sorbonne Université, INSERM UMRS_974, Center of Research in Myology, 75013 Paris, France. Electronic address: a.bertrand@institut-myologie.org.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2018 Mar 02; Vol. 10, pp. 376-386. Date of Electronic Publication: 2017 Dec 30.
DOI:	10.1016/j.omtn.2017.12.012
Abstrakt:	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. (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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