Antisense oligonucleotide development for the treatment of muscular dystrophies

ABSTRACT

Introduction: Depending upon the chemistry and annealing target, antisense oligonucleotides can be used to modify gene expression through several distinct modes of action. Originally used to down-regulate gene expression through specific induction of RNAse-H cleavage of an mRNA, antisense oligonucleotides can be designed to block initiation of translation, manipulate pre-mRNA processing, silence gene expression or act as antagomirs to sequester miRNAs.

Area covered: In this review, we describe currently available antisense oligonucleotide chemistries, briefly summarize mechanisms of action, potential applications to neuromuscular diseases and discuss the most clinically advanced antisense oligonucleotide application to muscular dystrophy, restoration of functional dystrophin expression in Duchenne muscular dystrophy.

Expert opinion: Antisense oligonucleotide chemistries that are excellent research tools may not necessarily be appropriate or safe for clinical application. Hypothesis-driven translational research demands that changes in target gene expression at both the RNA and protein levels, after administration of the antisense oligonucleotide, should be readily detectable. In ongoing clinical studies on Duchenne muscular dystrophy, it is only the phosphorodiamidate morpholino oligomer that results in unequivocal increases in muscle dystrophin. It is our opinion that these compounds could present new therapeutic opportunities for a number of otherwise untreatable conditions.

KEYWORDS:

• Antisense oligonucleotides
• antisense therapy
• exon skipping
• muscular dystrophies
• therapeutic alternative splicing

Acknowledgments

TL Bao thanks the Murdoch University International Postgraduate Scholarship (MIPS) scheme.