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Development of Antisense‐Mediated Exon Skipping as a Treatment for Duchenne Muscular Dystrophy
Author(s) -
Heemskerk Hans,
de Winter Christa L.,
van Ommen GertJan B.,
van Deutekom Judith C.T.,
AartsmaRus Annemieke
Publication year - 2009
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2009.04973.x
Subject(s) - exon skipping , duchenne muscular dystrophy , dystrophin , exon , antisense therapy , muscular dystrophy , mdx mouse , nonsense mutation , morpholino , splice , biology , medicine , bioinformatics , genetics , oligonucleotide , alternative splicing , mutation , gene , locked nucleic acid , zebrafish , missense mutation
Duchenne muscular dystrophy (DMD) is a severe muscle‐wasting disease caused by frame shifting and nonsense mutations in the dystrophin gene. Through skipping of an (additional) exon from the pre‐mRNA, the reading frame can be restored. This can be achieved with antisense oligonucleotides (AONs), which induce exon skipping by binding to splice sites or splice enhancer sites. The resulting protein will be shorter but at least partially functional. So far, exon skipping has been very successful in cell cultures, in mouse and dog models, and even in a first exploratory study in patients. Current research mainly focuses on optimization of systemic AON delivery. Here we give an overview of the available mouse models. To obtain the most informative results for future clinical application, research may have to move from the currently preferred mdx mouse to mouse models more comparable to patients, such as the utrophin/dystrophin‐negative mouse and the hDMD mouse models. Further, we briefly discuss two AON backbone chemistries that are currently in clinical trials for DMD exon skipping. We propose that different chemistries should be further developed in parallel in order to hasten the transfer of the exon skipping therapy to the clinic.