Rethinking antisense oligonucleotide therapeutics for amyotrophic lateral sclerosis

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Antisense oligonucleotides (ASOs) are emerging as a therapeutic strategy for proteinopathies.
• Clinical trials for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), have yielded mixed results.
• ASO efficacy in targeting specific disease mechanisms requires further investigation.

Purpose of the Study:

• To review the current status of antisense oligonucleotide treatments for amyotrophic lateral sclerosis (ALS).
• To discuss the challenges and prospects of ASO therapy in ALS.
• To explore reasons for the lack of clinical benefit despite target engagement.

Main Methods:

• Review of clinical trial data for tofersen targeting SOD1 mRNA in ALS.
• Analysis of case reports for ASO treatments in ALS patients with FUS and C9orf72 mutations.
• Discussion of potential mechanisms underlying ASO treatment outcomes.

Main Results:

• Tofersen treatment reduced SOD1 and neurofilament light chain levels but did not improve clinical endpoints in ALS.
• ASO treatments in FUS and C9orf72 mutation carriers showed target protein reduction but no clinical benefit.
• Proof of mechanism (target engagement) was demonstrated, but proof of concept (clinical efficacy) was not achieved.

Conclusions:

• Current ASO strategies for ALS demonstrate target engagement but lack clinical efficacy.
• Potential reasons for treatment failure include on-target adverse effects and irreversible neuronal damage.
• Further research is needed to optimize ASO therapy for ALS and other proteinopathies.