Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges

Virginia Arechavala-Gomeza, Karen Anthony, Jennifer Morgan, Francesco Muntoni

Research output: Contribution to journalArticle

Abstract

Duchenne muscular dystrophy (DMD) is the most common childhood neuromuscular disorder. It is caused by mutations in the DMD gene that disrupt the open reading frame (ORF) preventing the production of functional dystrophin protein. The loss of dystrophin ultimately leads to the degeneration of muscle fibres, progressive weakness and premature death. Antisense oligonucleotides (AOs) targeted to splicing elements within DMD pre-mRNA can induce the skipping of targeted exons, restoring the ORF and the consequent production of a shorter but functional dystrophin protein. This approach may lead to an effective disease modifying treatment for DMD and progress towards clinical application has been rapid. Less than a decade has passed between the first studies published in 1998 describing the use of AOs to modify the DMD gene in mice and the results of the first intramuscular proof of concept clinical trials. Whilst phase II and III trials are now underway, the heterogeneity of DMD mutations, efficient systemic delivery and targeting of AOs to cardiac muscle remain significant challenges. Here we review the current status of AO-mediated therapy for DMD, discussing the preclinical, clinical and regulatory hurdles and their possible solutions to expedite the translation of AO-mediated exon skipping therapy to clinic.
Original languageEnglish
Pages (from-to)152-160
Number of pages9
JournalCurrent Gene Therapy
DOIs
Publication statusPublished - 1 Jun 2012

Fingerprint

Duchenne Muscular Dystrophy
Antisense Oligonucleotides
Exons
Dystrophin
Open Reading Frames
Mutation
Premature Mortality
RNA Precursors
Genes
Myocardium
Proteins
Clinical Trials
Muscles
Therapeutics

Cite this

Arechavala-Gomeza, Virginia ; Anthony, Karen ; Morgan, Jennifer ; Muntoni, Francesco. / Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges. In: Current Gene Therapy. 2012 ; pp. 152-160.
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Antisense Oligonucleotide-Mediated Exon Skipping for Duchenne Muscular Dystrophy: Progress and Challenges. / Arechavala-Gomeza, Virginia; Anthony, Karen; Morgan, Jennifer; Muntoni, Francesco.

In: Current Gene Therapy, 01.06.2012, p. 152-160.

Research output: Contribution to journalArticle

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