Antisense Oligonucleotide Therapy for Amyotrophic Lateral Sclerosis (ALS): An Umbrella Review

TL;DR

This paper reviews the effectiveness of antisense oligonucleotide therapies for treating ALS, finding that only one treatment, Tofersen, has been approved so far.

Contribution

The paper provides an umbrella review of recent ASO therapies for ALS, highlighting the challenges and limited success in clinical applications.

Findings

Only one ASO therapy, Tofersen, has been approved for ALS, targeting the SOD1 gene mutation.

Most ASO treatments failed due to not meeting efficacy endpoints.

Sporadic ALS remains a significant challenge as it is more common than familial ALS.

Abstract

Amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease, is a fatal neurodegenerative disease prominent in the elderly population. To this point, no completely effective treatments have been procured; however, antisense oligonucleotide therapies, or ASOs, are a promising venue. In order to investigate the efficacy of ASOs in the treatment of ALS by targeting specific genetic mutations, we conducted an umbrella review utilizing keywords such as “ALS” and “ASO” in the PubMed database, excluding sources published more than 10 years ago for relevance. Results revealed that of multiple tentative ASO treatments, for multiple specific gene mutations, only one, Tofersen, was approved for the wider population. The main cause of failure was an inability to meet efficacy endpoints, resulting in the discontinuation of the product. Tofersen is able to treat mutations in the SOD1 gene, but not any others. While initially discouraging, the production of ASOs is a relatively new and advanced process, and slow progress is expected. However, there remains the problem of identifying and treating the much more prevalent sporadic ALS, which is much more common compared to familial ALS.

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