Duchenne muscular dystrophy is a severe, progressive muscle-wasting disease caused by the mutations that disrupt the reading frame of the dystrophin gene and abolishing production of functional dystrophin protein. Normally, dystrophin connects the cytoskeleton of muscle fibers to the extracellular matrix, thus providing stability during muscle contraction. Lacking dystrophin, muscle fibers of Duchenne patients are continuously damaged, leading to loss of muscle tissue and function. Interestingly, when mutations maintain the reading frame, internally deleted dystrophins can be produced that are partially functional. These dystrophins are associated with the less severe and less progressive Becker muscular dystrophy.<br/>The aim of the antisense-mediated exon skipping therapy is to allow Duchenne patients to produce Becker-like dystrophins, hoping this will slow down disease progression. Antisense oligonucleotides (ASOs) are small chemically modified RNA or DNA analogs that can manipulate dystrophin pre-mRNA splicing by hiding a target exon from the splicing machinery. This restores the reading frame allowing the production of a partially functional dystrophin, as found in Becker muscular dystrophy patients.<br/>Currently one exon skipping ASO has been approved for Duchenne therapy by the Food and Drug Administration. The presentation will outline the development of this approach through proof-of-concept studies in cell and animal models, preclinical optimization studies and clinical trials, but also discuss the lessons learnt by the field and the requirement for multilateral education of stakeholders (patients, regulators and academics) to develop tools to measure clinical efficacy of the approach. <br/>

Exon skipping therapy for Duchenne muscular dystrophy – it takes more than an antisense oligonucleotide

256th National Meeting (2018)

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