Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis

Abstract

Antisense oligonucleotides, which are used to silence target genes, are gaining attention as a novel drug discovery modality for proteinopathies. However, while clinical trials for neurodegenerative diseases like amyotrophic lateral sclerosis have been conducted in recent years, the results have not always been favorable. The results from a Phase III trial of the antisense oligonucleotide, that is, tofersen, which targets SOD1 mRNA, showed decreased levels of cerebrospinal fluid SOD1 and plasma neurofilament light chain but no improvements in primary clinical endpoint. Moreover, case reports pertaining to patients with amyotrophic lateral sclerosis carrying FUS and C9orf72 mutations who received antisense oligonucleotide-based treatments have demonstrated a notable reduction in the targeted protein (thus providing the proof of mechanism) but with no discernible clinical benefits. There are several possible reasons why antisense oligonucleotides knockdown fails to achieve proof of concept, which need to be addressed: on-target adverse effects resulting from the loss of function of target gene and irreversible neuronal death cascade due to toxic protein accumulation, among other factors. This review provides an overview of the current status and discusses the prospects of antisense oligonucleotides treatment for amyotrophic lateral sclerosis.

Figure 1

The promising mechanisms of ongoing ASOs in the pathophysiology of ALS. Silencing of target genes by tofersen, ulefnersen, BIIB078, and nL‐CHCHD‐001 reduces toxic protein aggregation of SOD1, FUS, dipeptide repeat proteins, and CHCHD10, respectively. In TDP‐43‐ALS, silencing of the modulator of TDP‐43, ataxin2, by BIIB105 reduces TDP‐43 aggregation. A splicing switch of STMN2 using QRL‐201 results in the production of a full‐length STMN2 and normal axonal outgrowth. Abbreviations: ALS, amyotrophic lateral sclerosis; ASO, antisense oligonucleotides; C9‐ALS, ALS with C9orf72 mutation; FUS‐ALS, ALS with FUS mutation; SOD1‐ALS, ALS with SOD1 mutation; CHCHD10‐ALS, ALS with CHCHD10 mutation.