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Antisense oligonucleotides (ASOs) are modified nucleic acids that alter gene expression in cells by binding target mRNA in a sequence-specific manner. ASO binding can trigger degradation or alter processing of mRNA. Potential advantages of this class of therapeutic include specificity (from base pairing), amplification of effect (one ASO can catalyse the degradation/processing of many mRNAs), and reversibility (in contrast to gene therapies acting on DNA). Many neurodegenerative diseases have either a direct genetic cause or a phenotype that is modified by genetic variation making them ideal candidates for ASO therapeutics. In practice, developing effective ASOs for neurological disease has been difficult: targeting to the appropriate part of the central nervous system (CNS) is problematic and early ASOs had short half-lives and significant inflammatory side effects. However, advances in ASO chemistry over the last 20 years have improved the pharmacodynamic, pharmacokinetic, and side-effect profiles of these drugs which are now being trialled in a range of conditions, with promising early results. This month’s journal club examines three papers involving ASO therapeutics in neurodegeneration. The first two papers look at amyotrophic lateral sclerosis (ALS): one using cell/animal models to show the utility of ASOs and the other demonstrating the safety of intrathecal ASOs in humans. The third paper reports the exciting success of ASO therapy in treating spinal muscular atrophy (SMA).

Why antisense could make sense for neurodegeneration