Antisense Oligonucleotides for the Study and Treatment of ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss. ALS is now associated with mutations in numerous genes, many of which cause disease in part through toxic gain-of-function mechanisms. Antisense oligonucleotides (ASOs) are small sequences of DNA that can reduce expression of a target gene at the post-transcriptional level, making them attractive for neutralizing mutant or toxic gene products. Advancements in the medicinal chemistries of ASOs have improved their pharmacodynamic profile to allow safe and effective delivery to the central nervous system. ASO therapies for ALS have rapidly developed over the last two decades, and ASOs that target SOD1, C9orf72, FUS, and ATXN2 are now in clinical trials for familial or sporadic forms of ALS. This review discusses the current state of ASO therapies for ALS, outlining their successes from preclinical development to early clinical trials.

Keywords: Amyotrophic lateral sclerosis; Antisense oligonucleotide; Clinical trials; Motor neuron disease; Therapy.

Fig. 1

Antisense oligonucleotide therapies under investigation in preclinical studies and human clinical trials for amyotrophic lateral sclerosis. ASO candidates targeting genes associated with ALS, including SOD1 [–31, 45, 46], C9orf72 [–, –74], FUS [85], and ATXN2 [99], have demonstrated target efficacy, distribution throughout the central nervous system, and a strong safety profile. ASOs depicted target the human form of the gene and have been tested in preclinical and/or clinical trials (see references for more detail). ASO depictions do not represent exact binding locations. Note: the binding site of WVE-004 within the C9orf72 gene [71] is not included in this figure. Figure created with BioRender.com

Fig. 2

Antisense oligonucleotide-mediated degradation of a gene target. Once delivered to the cerebrospinal fluid, antisense oligonucleotides (ASOs) are taken up into cells and can enter the nucleus. ASOs then bind to their gene target in a complementary fashion, creating a RNA–DNA hybrid that recruits the enzyme RNase H to cleave the target RNA. This action results in degradation of the gene target but spares the ASO, allowing it to persist in the cell. Without the RNA template, the gene will not be translated into protein, and the protein product is reduced over time. ASO therapeutics under investigation for amyotrophic lateral sclerosis (ALS) commonly employ this RNA-degrading strategy. Figure created with BioRender.com