Dystrophin rescue by trans -splicing: a strategy for DMD genotypes not eligible for exon skipping approaches

Stéphanie Lorain; Cécile Peccate; Maëva Le Hir; Graziella Griffith; Susanne Philippi; Guillaume Précigout; Kamel Mamchaoui; Arnaud Jollet; Thomas Voit; Luis Garcia

doi:10.1093/nar/gkt621

Dystrophin rescue by trans -splicing: a strategy for DMD genotypes not eligible for exon skipping approaches

Nucleic Acids Research ◽

10.1093/nar/gkt621 ◽

2013 ◽

Vol 41 (17) ◽

pp. 8391-8402 ◽

Cited By ~ 25

Author(s):

Stéphanie Lorain ◽

Cécile Peccate ◽

Maëva Le Hir ◽

Graziella Griffith ◽

Susanne Philippi ◽

...

Keyword(s):

Exon Skipping ◽

Trans Splicing

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T.I.5 Re-establishment of dystrophin expression by exon skipping and/or trans-splicing approaches

Neuromuscular Disorders ◽

10.1016/j.nmd.2008.06.375 ◽

2008 ◽

Vol 18 (9-10) ◽

pp. 831

Author(s):

L. Garcia

Keyword(s):

Exon Skipping ◽

Dystrophin Expression ◽

Trans Splicing

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Prospects for the Etiotropic Treatment of Dysferlinopathy

Annals of the Russian academy of medical sciences ◽

10.15690/vramn1379 ◽

2021 ◽

Vol 76 (3) ◽

pp. 307-316

Author(s):

Alisa V. Ivanova ◽

Svetlana A. Smirnikhina ◽

Alexander V. Lavrov

Keyword(s):

Stop Codon ◽

Experimental Studies ◽

Neuromuscular Diseases ◽

Exon Skipping ◽

Autosomal Recessive Inheritance ◽

Primary Lesion ◽

Muscular Dystrophies ◽

Human Skeletal Muscle Cells ◽

Anterior Tibial ◽

Trans Splicing

Dysferlinopathies belong to a phenotypically heterogeneous group of neuromuscular diseases caused by mutations in the DYSF gene, which disrupt the expression of dysferlin protein in human skeletal muscle cells. These pathologies are of an autosomal recessive inheritance pattern, their prevalence is 1: 200000. Dysferlinopathies include diseases such as Miyoshi myopathy with primary lesion of the distal fragments of the lower extremities and limb-gridle muscular dystrophy type 2B with primary lesion of the proximal fragments of both the lower and upper limbs, also distal myopathy with anterior tibial onset (DMAT). Nowdays, there are various pathogenetic and symptomatic treatments for hereditary muscular dystrophies but there are very few registered drugs for the etiological treatment of these diseases. This review discusses the main modern methods of gene therapy that can be used to treat dysferlinopathies, such as stop-codon passing, exon skipping, overexpression of other genes, gene transfer, splicosome-mediated trans-splicing, and also describes the latest experimental studies using these methods. In conclusion, exon-skipping and trans-splicing have been identified as the most optimal approaches in the treatment of muscular dystrophies, in particular dysferlinopathies.

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Muskeldystrophie Typ Duchenne

Nervenheilkunde ◽

10.1055/s-0038-1628428 ◽

2011 ◽

Vol 30 (10) ◽

pp. 805-812

Author(s):

A. von Moers

Keyword(s):

Exon Skipping ◽

Phase Iii ◽

Muskeldystrophie Duchenne

ZusammenfassungDie Muskeldystrophie Duchenne ist eine X-gebundene rezessive Erkrankung, die bei 1:3 500 Knaben auftritt. Sie wird durch Mutationen im DMD-Gen verursacht. Die Mutationen resultieren in einem Verlust von Dystrophin, dies führt zur progredienten Muskeldegeneration. Der Krankheitsverlauf ist durch eine progrediente, proximal betonte Muskelschwäche gekennzeichnet, die ohne Behandlung zu einem Gehverlust um das 10. Lebensjahr und zum frühzeitigen Tod um das 20. Lebensjahr durch Ateminsuffizienz oder Herzversagen führt. Durch symptomatische Therapien kann der Krankheitsverlauf positiv beeinflusst werden, besonders durch die Etablierung der nicht invasiven Beatmung konnte die Lebenserwartung erheblich verlängert werden. In den letzten Jahren wurden verschiedene Ansätze einer kausalen Therapie untersucht. Am weitesten gediehen ist das “exon skipping”, dessen Wirksamkeit in internationalen, multizentrischen Phase-III Studien untersucht wird.

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