Targeting RNA to treat neuromuscular disease

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Abstract
Neuromuscular disorders comprise a heterogeneous group of clinical conditions that primarily affect one or more components of the neuromuscular unit — typically skeletal muscle — but are often also multisystemic. The considerable clinical impact of these diseases is exemplified by the muscular dystrophies and by spinal muscular atrophy (SMA), for which the development for novel molecular therapies is both urgent and challenging. Recent advances in RNA biology have accelerated the progress of a new generation of molecular therapies based on RNA. Single- or double-stranded nucleic acid agents and small-molecule agents are being developed as novel therapies to target the mutant mRNAs that are involved in neuromuscular disease. These approaches modulate pre-mRNA processing or inhibit the deleterious effects of toxic RNAs. In the case of Duchenne muscular dystrophy (DMD), exon-skipping therapies to restore a viable open reading frame in the DMD gene are well advanced. Two recent systemic delivery clinical trials have reported encouraging data on the restoration of dystrophin protein expression, and second-generation compounds are in development. An alternative approach to stimulate the readthrough of premature stop codons, which is applicable to a subset of patients with DMD, is also in development. Myotonic dystrophy arises as a result of an expanded microsatellite repeat mutation that leads to a gain-of-function toxic mRNA, which ultimately causes muscle degeneration and multisystem dysfunction. Various approaches to correct the deleterious toxic effects of toxic RNA using small-molecule-based, oligonucleotide-based or RNA interference-based methods to inhibit or degrade the toxic RNA are being investigated. A viable therapeutic strategy for SMA, which arises as a result of the loss-of-function of the survival of motor neuron 1 (SMN1) gene, is to restore the splicing of exon 7 in the related SMN2 gene, which has the potential to fully compensate for the loss of the SMN1 protein. Recent studies using oligonucleotide-mediated exon-inclusion methods appear to be highly promising. Although the development of RNA-based therapies for neuromuscular disease remains challenging, recent progress in this field is encouraging. However, major barriers remain the poor in vivo delivery of most RNA therapeutic agents and the regulatory hurdles that are associated with the development of novel personalized medicines.