Antisense oligonucleotide drugs for Duchenne muscular dystrophy: how far have we come and what does the future hold?

Abstract

What is the current status of Duchenne muscular dystrophy therapy? Duchenne muscular dystrophy (DMD) is a devastating disease and the most prevalent lethal genetic disorder worldwide [1]. DMD is an X-linked recessive genetic disorder mostly caused by frame-shift mutations in the DMD gene, which disrupts the translational reading frame, resulting in a lack of dystrophin protein [2]. The lack of dystrophin, a muscle supporting protein, leads to lethal muscle wasting in DMD patients [3]. Due to advances in clinical management, specifically with pulmonary intervention, DMD patient survival has been prolonged, although most patients develop dilated cardiomyopathy eventually, and die from cardiac or respiratory failure by 30 years of age. Currently there is no cure for DMD patients, with treatment strategies being limited to glucocorticoid corticosteroids. DMD trials using corticosteroids found that there was an overall improvement in muscle strength as well as prolonged ambulation in the short term (6 months to 2 years) [4]. However, this treatment strategy also presented various limitations with its use. Presently, glucocorticoids have harsh side effects such as impaired growth and increased susceptibility to infection. Although glucocorticoid treatment has shown potential value in DMD, other treatment options are heavily being explored. Does antisense therapy hold the key? Recently, antisense-mediated exon-skipping therapy has emerged as a promising strategy for the treatment of DMD [5]. Antisense therapy is a strategy that uses short DNAlike molecules called antisense oligonucleotides (AONs) to selectively hybridize to nascent pre-mRNA, in order to correct various genetic diseases via exon skipping, splice modulation or by inhibiting gene expression [5]. In DMD, antisense-mediated exon skipping is currently one of the most promising treatment options. AONs can be used to restore the open reading frame, by establishing expression of a truncated but functional dystrophin, seen similarly in Becker muscular dystrophy, its milder counterpart [5]. Becker muscular dystrophy although commonly arising from mutations in the DMD gene retains its ability to produce partially functional dystrophin protein, due to inframe mutations that maintain the reading frame [5]. Antisense therapy, although currently promising as a treatment option for various disorders, has had slow success. Antisensemediated RNA regulation, which was first observed in nature, has greatly improved since the late 1970s, after Zamecnik et al. demonstrated that a gene expression can be inhibited by transfection of a short antisense (complementary) DNA sequence [6]. Antisense oligonucleotide drugs for Duchenne muscular dystrophy: how far have we come and what does the future hold?