RNA antisense and silencing strategies using synthetic drugs for rare muscular and neuromuscular diseases

Abstract

Rare diseases occur in their large majority from a genetic cause, which makes them good candidates for genetic RNA drugs. The basic concepts, principles, mechanisms of action and chemical optimizations of synthetic antisense oligonucleotides (ASO) and small interfering RNA (siRNA) are illustrated. These drugs act either by leading to RNA degradation, or as steric blockers of RNA translation, microRNA antagonists, splicing modulators or inducers of exon skipping. Chemical modifications and delivery techniques differ and are adapted to their distinct functions. The successes, potential, and challenges of synthetic RNA drugs are illustrated for several muscular and neuromuscular diseases: Duchenne muscular dystrophy, spinal muscular atrophy, transthyretin amyloidosis, Type 1 myotonic dystrophy, centronuclear myopathy, oculopharyngeal muscular dystrophy.