Therapeutic antisense oligonucleotides for movement disorders

Movement disorders are a group of neurological conditions characterized by abnormalities of movement and posture. They are broadly divided into akinetic and hyperkinetic syndromes. Until now, no effective symptomatic or disease-modifying therapies have been available. However, since many of these disorders are monogenic or have some well-defined genetic component, they represent strong candidates for antisense oligonucleotide (ASO) therapies. ASO therapies are based on the use of short synthetic single-stranded ASOs that bind to disease-related target RNAs via Watson-Crick base-pairing and pleiotropically modulate their function. With information arising from the RNA sequence alone, it is possible to design ASOs that not only alter the expression levels but also the splicing defects of any protein, far exceeding the intervention repertoire of traditional small molecule approaches. Following the regulatory approval of ASO therapies for spinal muscular atrophy and Duchenne muscular dystrophy in 2016, there has been tremendous momentum in testing such therapies for other neurological disorders. This review article initially focuses on the chemical modifications aimed at improving ASO effectiveness, the mechanisms by which ASOs can interfere with RNA function, delivery systems and pharmacokinetics, and the common set of toxicities associated with their application. It, then, describes the pathophysiology and the latest information on preclinical and clinical trials utilizing ASOs for the treatment of Parkinson's disease, Huntington's disease, and ataxias 1, 2, 3, and 7. It concludes with issues that require special attention to realize the full potential of ASO-based therapies.