Exon Skipping
Prosensa’s exon skipping technology is directed at interference with exon inclusion signals within an exon during the splicing of the pre-mRNA, in order to prevent the incorporation of the targeted exon in the mature RNA. This selective removal of (mutated) exons increases the level of functional transcripts and reverse disease symptoms.
Duchenne Muscular Dystrophy (DMD) is caused by mutations in the DMD gene, mostly deletions of 1 or more exons (~72%) that disrupt the open reading frame of the transcript and prematurely abort the synthesis of the dystrophin protein. Patients with Becker Muscular Dystrophy (BMD) show intermediate to milder phenotypes with mostly longer to normal life expectancies when compared with DMD patients. Here, the mutations in the DMD gene maintain the open reading frame and result in an internally truncated but semi-functional dystrophin. The specific skipping of 1 or more exons flanking the specific deletion in DMD patients allows restoration of the mutated open reading frame, introduction of novel, BMD-like dystrophin, and conversion of a severe DMD into a typically milder BMD phenotype.
Schematic representation of the exon-skipping strategy
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This DMD patient exhibits a deletion of exon 50 resulting in an out-of-frame mRNA transcript and a prematurely aborted dystrophin synthesis.
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Employing antisense oligonucleotide in exon 51 (PRO051/GSK2402968) binding to the pre-mRNA an in frame mRNA transcript is produced resulting in a shortened BMD-type dystrophin protein.
Although exon skipping is a mutation-specific therapy, and providing personalized medicine, an important intrinsic advantage compared with conventional gene therapy is that it simultaneously corrects all dystrophin isoforms. It also maintains the original tissue-specific gene regulation. Moreover, the antisense compounds inducing exon skipping are small, synthetic, and highly sequence-specific.