Antisense oligonucleotides: the next frontier for treatment of neurological disorders

Key Points

  • Antisense oligonucleotides (ASOs) are short, synthetic, single-stranded oligodeoxynucleotides that can alter RNA and reduce, restore, or modify protein expression through several distinct mechanisms

  • By targeting the source of the pathogenesis, ASO-mediated therapies have an higher chance of success than therapies targeting downstream pathways

  • Advances in the understanding of ASO pharmacology have provided momentum for translating these therapeutics into the clinic

  • Two ASO-mediated therapies have received approval from the US Food and Drug Administration for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy

  • Further advancement of ASOs in the clinic urgently requires optimization of ASO delivery, target engagement, and safety profile

  • This technology holds the potential to change the therapeutic landscape for many neurological and non-neurological conditions in the near future

Abstract

Antisense oligonucleotides (ASOs) were first discovered to influence RNA processing and modulate protein expression over two decades ago; however, progress translating these agents into the clinic has been hampered by inadequate target engagement, insufficient biological activity, and off-target toxic effects. Over the years, novel chemical modifications of ASOs have been employed to address these issues. These modifications, in combination with elucidation of the mechanism of action of ASOs and improved clinical trial design, have provided momentum for the translation of ASO-based strategies into therapies. Many neurological conditions lack an effective treatment; however, as research progressively disentangles the pathogenic mechanisms of these diseases, they provide an ideal platform to test ASO-based strategies. This steady progress reached a pinnacle in the past few years with approvals of ASOs for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy, which represent landmarks in a field in which disease-modifying therapies were virtually non-existent. With the rapid development of improved next-generation ASOs toward clinical application, this technology now holds the potential to have a dramatic effect on the treatment of many neurological conditions in the near future.

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Figure 1: Chemical modifications of the ASO backbone.
Figure 2: Functional mechanisms of ASOs.

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C.R. declares no competing interests. M.J.A.W., through the University of Oxford, has filed patents on peptide-based methods for antisense oligonucleotide delivery.

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Rinaldi, C., Wood, M. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol 14, 9–21 (2018). https://doi.org/10.1038/nrneurol.2017.148

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