Eteplirsen

Dystrophin is a membrane-associated protein that links cytoskeletal actin in muscle fibres with the surrounding extracellular matrix by forming a network with sarcolemmal glycoproteins. This linkage strengthens muscle structure during stressful contraction and relaxation cycles. The loss of dystrophin leads to mechanical damage of muscle fibres and eventually muscle degeneration. Duchenne muscular dystrophy (DMD) is caused by deletion mutations in exons 43 to 55 of the DMD gene coding for dystrophin, which is the largest known human gene. These mutations disrupt the open reading frame and cease the normal production of dystrophin. About 60% of DMD cases are caused by deletions of at least one exon in DMD and about 13-14% of patients with DMD have exon 51 amenable deletions. Deletions ending at exon 50 and starting at exon 52 represents the largest group of patients to which single exon skipping is applicable.

Eteplirsen mediates its effect by inducing exon skipping in defective gene variants. Eteplirsen selectively binds to exon 51 of dystrophin pre-mRNA, excluding this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Through exon skipping, eteplirsen restores the open reading frame of the DMD gene and allows the production of functional dystrophin.