Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Mutations in superoxide dismutase 1 (SOD1) cause 20% of familial amyotrophic lateral sclerosis (ALS).
• A toxic gain-of-function mechanism in SOD1-linked ALS suggests therapeutic benefit from reducing SOD1 mRNA and protein levels.
• Previous antisense oligonucleotide (ASO) therapies showed potential but were superseded by more advanced designs.

Purpose of the Study:

• To develop and evaluate next-generation SOD1-targeting antisense oligonucleotides (ASOs) for potential therapeutic application in SOD1-familial ALS.
• To assess the efficacy of these novel ASOs in reducing SOD1 levels and improving outcomes in preclinical models of ALS.

Main Methods:

• Development of potent, next-generation SOD1-targeting ASOs.
• Administration of SOD1 ASOs to SOD1G93A rats and mice models of ALS.
• Assessment of SOD1 mRNA and protein levels, survival rates, compound muscle action potential, and serum phospho-neurofilament heavy chain levels.

Main Results:

• Next-generation SOD1 ASOs significantly reduced SOD1 mRNA and protein levels.
• Therapy extended survival by over 50 days in rats and nearly 40 days in mice.
• A single dose reversed loss of compound muscle action potential and halted increases in a key ALS biomarker.

Conclusions:

• The developed SOD1 ASOs are highly potent and demonstrate significant therapeutic potential in preclinical ALS models.
• These findings support the advancement of this novel SOD1 ASO therapy into human clinical trials.
• The results suggest that SOD1 ASO therapy can reverse certain aspects of muscle dysfunction in ALS.