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Mansi Gandhi

Skip, walk and jump

Rare diseases and the power of precision medicine

When molecular biologists Steve Wilton and Sue Fletcher first started exploring dystrophin exon skipping for Duchenne muscular dystrophy (DMD), they faced a lot of scepticism.

F

ast forward 20 years, and the drug

developed by the researchers has altered disease progression — dramatically improving the quality of life of DMD sufferers. Strong support from the local Western Australian and US-based Muscular Dystrophy Association was a powerful motivator. Caused by mutations in the DMD gene, the disorder affects 1 in 5000 males around the world, according to Muscular Dystrophy Western Australia. The disorder typically affects boys but girls can be carriers and in very rare instances present with the disease. Symptoms include delayed walking, inability of children to run and jump, followed by progressive muscle weakness and breathing difficulties. The dystrophin gene has 79 exons spanning 2.3 megabases. In the severe forms of DMD, there is a protein truncating mutation so the end of gene message is missing — these kids have the most severe phenotype and typically become wheelchair bound before the age of 12, explained Wilton. One of the most common types of mutation in this gene is a deletion of one or more exons. If a deletion disrupts the reading frame, the result is Duchenne but if the deletion maintains the reading frame, the consequence is Becker muscular dystrophy, a milder form of the disease. The drug developed by Wilton and Fletcher, now at Murdoch University, is designed to skip over the disease causing part of the gene message and reframe the message. For example, if a patient is missing exon 50, the reading frame is lost and the message is terminated in exon 51. © stock.adobe.com/au/photophonie

Hence, by skipping exon 51, the early stop signal is ‘skipped over’ during splicing and the reading frame is restored. This is the first splice switching drug to address the underlying genetic defect of Duchenne, and the first of its type to be approved by the US Food and Drug Administration (FDA), according to Wilton. The rights to develop the

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