The Journal of Clinical Investigation Publishes Preclinical Data Demonstrating Robust Potency and Efficacy of SOD1 Antisense Oligonucleotides in ALS Models

-Latest SOD1-targeting antisense oligonucleotides potently reduce SOD1 mRNA and protein-

-Delayed disease onset, extended survival, and improvement in motor performance observed in ALS models-

Positive preclinical data for antisense oligonucleotides targeting the production of superoxide dismutase 1 (SOD1) were recently published in The Journal of Clinical Investigation in a paper titled, “Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models.” The results show extended pharmacology and improved potency compared to the original SOD1-targeting antisense drug previously studied. The new antisense oligonucleotides significantly delayed disease onset, extended survival, and demonstrated reversal of SOD1-mediated neuronal dysfunction.

Amyotrophic lateral sclerosis, or ‎ALS, is a rare, fatal neurodegenerative disorder characterized by loss and dysfunction of neurons in motor pathways. People with ALS suffer progressive degeneration of motor neurons, which results in difficulties in ambulatory movement, speech and respiration, and ultimately death.  SOD1-targeting antisense drugs present a potential therapeutic opportunity to treat SOD1-ALS. Genetic mutations are responsible for approximately 15-20% of ALS cases. In approximately 20% of these cases, a mutation in the SOD1 gene results in an inherited form of ALS, referred to as SOD1-ALS. While the exact toxicity is not completely understood, it is predicted that lowering SOD1 mRNA and protein levels will provide a therapeutic benefit.

Scientists at Biogen, Ionis Pharmaceuticals, Washington University School of Medicine and Harvard Medical School demonstrated the efficacy of SOD1-targeting antisense oligonucleotides with robust preclinical data demonstrating:

  • Good distribution of the SOD1-targeting antisense oligonucleotides throughout the brain and spinal cord in animal models, including non-human primates.
  • Reduced levels of human SOD1 mRNA and protein by approximately 75% following a single injection in transgenic mice.
    • Non-human primate models also demonstrated dose-dependent reductions of SOD1 mRNA and protein.
    • Important markers of ALS, compound muscle action potential (CMAP) and neuromuscular innervation, were stable following a single dose.
    • Another biomarker of the disease, serum levels of phospho-neurofilament heavy chain (pNFH), was lowered indicating decreased neurodegeneration.
  • Significantly delayed disease onset in rodent models.
    • Survival was extended by up to 22% in mouse models and up to 39% in rat models.
    • Reversal of neuronal dysfunction was seen in SOD1 ALS, as measured by reversed CMAP amplitude and lowered pNFH levels.

Given the promising results of these preclinical studies, a clinical trial is already underway to evaluate the safety and efficacy of the more potent SOD1-targeting antisense drug, IONIS-SOD1Rx. Notably, in preclinical studies, the new drug demonstrated improved activity compared to the original drug and has the potential to provide a major advance in the current treatment paradigm of SOD1 ALS.


  1. McCampbell et al., “Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models.” The Journal of Clinical Investigations, Advanced Online Publication, July 16, 2018 (link: