Current Status of Antisense Oligonucleotide-Based Therapy in Neuromuscular Disorders
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REVIEW ARTICLE
Current Status of Antisense Oligonucleotide‑Based Therapy in Neuromuscular Disorders Flavien Bizot1 · Adeline Vulin‑Chaffiol1,2 · Aurélie Goyenvalle1,3
© Springer Nature Switzerland AG 2020
Abstract Neuromuscular disorders include a wide range of diseases affecting the peripheral nervous system, which are primarily characterized by progressive muscle weakness and wasting. While there were no effective therapies until recently, several therapeutic approaches have advanced to clinical trials in the past few years. Among these, the antisense technology aiming at modifying RNA processing and function has remarkably progressed and a few antisense oligonucleotides (ASOs) have now been approved. Despite these recent clinical successes, several ASOs have also failed and clinical programs have been suspended, in most cases when the route of administration was systemic, highlighting the existing challenges notably with respect to effective ASO delivery. In this review we summarize the recent advances and current status of antisense basedtherapies for neuromuscular disorders, using successful as well as unsuccessful examples to highlight the variability of outcomes depending on the target tissue and route of administration. We describe the different ASO-mediated therapeutic approaches, including splice-switching applications, steric-blocking strategies and targeted gene knock-down mediated by ribonuclease H recruitment. In this overview, we discuss the merits and challenges of the current ASO technology, and discuss the future of ASO development.
Key Points
1 Introduction
Antisense oligonucleotides (ASOs) hold great promise as a therapeutic platform for the treatment of neuromuscular disorders.
Antisense oligonucleotide (ASO)-based therapeutics have made tremendous progress in the last 20 years and the recent approval of several drugs has increased the interest in the field even more. ASOs are typically synthetic single-stranded oligonucleotides of 12–30 nucleotides long [1–3], designed to bind to a messenger RNA (mRNA) or non-coding RNA through Watson–Crick base pairing in order to modulate their function/expression. ASOs were first used in 1978 by Zamecnik and Stephenson as a gene-silencing approach [4], but the technology has rapidly evolved since then with numerous other possible applications making them a valuable tool for genetic-based therapeutics [5]. While the first unmodified ASOs, which were composed of a phosphodiester backbone and sugar rings, were rapidly degraded within cells and the bloodstream [6], various modifications have progressively been introduced in their chemical structure in order to protect them from nuclease activity and increase their stability and affinity to target RNA [6]. One of the first modifications introduced was the replacement of one of the non-bridging oxygen atoms in the phosphate group with a sulphur atom resulting in phosphorothioate (PS) ASO. This substitution
The clinical benefit of ASO-therapy still highly depends on the target tissue and route of adminis
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