Antisense oligonucleotides in neurological disorders

Therapeutic Advances in Neurological Disorders
Claudia D Wurster, Albert C Ludolph

Abstract

The introduction of genetics revolutionized the field of neurodegenerative and neuromuscular diseases and has provided considerable insight into the underlying pathomechanisms. Nevertheless, effective treatment options have been limited. This changed recently when antisense oligonucleotides (ASOs) could be translated from in vitro and experimental animal studies into clinical practice. In 2016, two ASOs were approved by the United States US Food and Drug Administration (FDA) and demonstrated remarkable efficacy in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA). ASOs are synthetic single-stranded strings of nucleic acids. They selectively bind to specific premessenger ribonucleic acid (pre-mRNA)/mRNA sequences and alter protein synthesis by several mechanisms of action. Thus, apart from gene replacement, ASOs may therefore provide the most direct therapeutic strategy for influencing gene expression. In this review, we shall discuss basic mechanisms of ASO action, the role of chemical modifications needed to improve the pharmacodynamic and pharmacokinetic properties of ASOs, and we shall then focus on several ASOs developed for the treatment of neurodegenerative and neuromuscular disorders, including SMA, DMD...Continue Reading

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Methods Mentioned

BETA
antisense oligonucleotide
antisense oligonucleotides
SMA
biopsies
transgenic

Clinical Trials Mentioned

NCT01494701
NCT01780246
NCT01839656
NCT02193074
NCT02292537
NCT02594124
NCT02386553
NCT02122952
NCT01153932
NCT00159250

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