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

Abstract : 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 0-RNA pretrans-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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https://hal.sorbonne-universite.fr/hal-03269960
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Submitted on : Thursday, June 24, 2021 - 2:30:00 PM
Last modification on : Tuesday, July 13, 2021 - 3:28:14 AM

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Feriel Azibani, Astrid Brull, Ludovic Arandel, Maud Beuvin, Isabelle Nelson, et al.. Gene Therapy via Trans-Splicing for LMNA-Related Congenital Muscular Dystrophy. Molecular Therapy - Nucleic Acids, Nature Publishing Group, 2018, 10, pp.376 - 386. ⟨10.1016/j.omtn.2017.12.012⟩. ⟨hal-03269960⟩

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