Exon Skipping and Duchenne Muscular Dystrophy Therapy: Selection of the Most Active U1 SnRNA Antisense Able to Induce Dystrophin Exon 51 Skipping

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2010 Jun 17

PMID 20551908

Citations 16

Authors

Tania Incitti

Fernanda G De Angelis

Valentina Cazzella

Olga Sthandier

Chiara Pinnaro

Ivano Legnini

Irene Bozzoni

Affiliations

Soon will be listed here.

Abstract

One promising approach for the gene therapy of Duchenne muscular dystrophy (DMD) is exon skipping. When thinking of possible intervention on human, it is very crucial to identify the most appropriate antisense sequences able to provide the highest possible skipping efficiency. In this article, we compared the exon 51 skipping activity of 10 different antisense molecules, raised against splice junctions and/or exonic splicing enhancers (ESEs), expressed as part of the U1 small nuclear RNA (snRNA). The effectiveness of each construct was tested in human DMD myoblasts carrying the deletion of exons 48-50, which can be treated with skipping of exon 51. Our results show that the highest skipping activity and dystrophin rescue is achieved upon expression of a U1 snRNA-derived antisense molecule targeting exon 51 splice sites in combination with an internal exon sequence. The efficacy of this molecule was further proven on an exon 45-50 deletion background, utilizing patient's fibroblasts transdifferentiated into myoblasts. In this system, we showed that the selected antisense was able to produce 50% skipping of exon 51.

Citing Articles

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Goncalves M, Santos J, Coutinho M, Matos L, Alves S Int J Mol Sci. 2023; 24(19).

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Exon Skipping Through Chimeric Antisense snRNAs to Correct Retinitis Pigmentosa GTPase-Regulator () Splice Defect.

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Trans-generational epigenetic regulation associated with the amelioration of Duchenne Muscular Dystrophy.

Martone J, Lisi M, Castagnetti F, Rosa A, Di Carlo V, Blanco E EMBO Mol Med. 2020; 12(8):e12063.

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Double-target Antisense U1snRNAs Correct Mis-splicing Due to c.639+861C>T and c.639+919G>A GLA Deep Intronic Mutations.

Ferri L, Covello G, Caciotti A, Guerrini R, Denti M, Morrone A Mol Ther Nucleic Acids. 2016; 5(10):e380.

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