Potential ALS Therapy Boosts Survival, Reverses Neuromuscular Damage in Animal Study

The investigational treatment could benefit patients with amyotrophic lateral sclerosis whose disease is caused by mutations in the SOD1 gene.

An investigational therapy for an inherited form of amyotrophic lateral sclerosis (ALS) boosted survival and reversed some neuromuscular damage in animals, according to new research published in The Journal of Clinical Investigation.

Researchers from the Washington University School of Medicine investigated whether the experimental treatment could be beneficial to patients with ALS whose disease is caused by mutations in a gene called SOD1. For the study, mice and rats were genetically modified to carry a mutated form of the human SOD1 gene.

Mutations in the SOD1 gene cause approximately 1/5 of inherited ALS cases, according to the researchers. This gene mutation causes the SOD1 protein to be overly active, which suggests that reducing protein levels may benefit patients with ALS caused by these mutations, they wrote.

The researchers tested 2 DNA-based compounds, known as antisense oligonucleotides, or oligos for short, which block the body from making the SOD1 protein. At day 50, mice were given an anti-SOD1 oligo or a placebo. A second dose was administered approximately 6 weeks later.

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According to the study, the mice that received the active drug maintained their weight 26 days longer and lived 37 days longer than those given the placebo. Rats that received an active oligo maintained their weight more than 9 weeks longer and survived 8 to 9 weeks longer compared with rats administered the placebo.

“This drug had an impressive effect in mice and rats with just 1 or 2 doses,” study author Timothy Miller, MD, PhD, the David Clayson Professor of Neurology at Washington University, said in a press release. “We don’t know yet if this works in people, but we’re very hopeful.”

The researchers also found that the oligos reversed the signs of neuromuscular damage after being given to the animals. In mice with the mutant SOD1 gene who were already showing molecular signs of deteriorating neuromuscular function, muscle function steadily improved over the 8-week period after receiving an anti-SOD1 oligo while mice given the placebo showed a steady decline. Although signs of neuromuscular damage increased in both groups, it rose more than twice as quickly in the mice that were not treated with the active oligo.

The findings have led to a phase 1/2 clinical trial evaluating the safety of the therapy in humans, according to the researchers.

“The phase 1/2 trial is really still a safety trial,” Dr Miller said in the press release. “There are not enough patients in it to really be able to accurately see an effect on disease. But we’re on the cusp of testing the hypothesis that people with ALS caused by mutations in SOD1 can benefit from this treatment. We predict the effect will be good, but we can’t know until we test it.”


McCampbell A, Cole T, Wegener AJ, et al. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. The Journal of Clinical Investigation. 2018. Doi: 10.1172/JCI99081

New ALS therapy in clinical trials [news release]. Washington University School of Medicine’s website. https://medicine.wustl.edu/news/new-als-therapy-in-clinical-trials/. Accessed July 17, 2018.