Moving towards genomic therapy for amyotrophic lateral sclerosis

Superoxide dismutase 1 (SOD1) gene mutations account for up to 20% of cases of familial amyotrophic lateral sclerosis (ALS), and this gene could represent an important therapeutic target. Two new reports in The New England Journal of Medicine provide early indications that knockdown of SOD1 expression is feasible and warrants further exploration in people with SOD1 ALS.

The first study used the antisense oligonucleotide (ASO) tofersen to target SOD1. “ASOs bind to the target mRNA and activate RNAse H, which degrades the mRNA,” explains lead author Timothy Miller. “As mutations in SOD1 cause a toxic gain of function, lowering the levels of SOD1 protein is predicted to be therapeutic.”

The phase I/II trial included 50 patients with SOD1 ALS, 48 of whom completed the treatment course. The participants were randomly assigned to tofersen (20, 40, 60 or 100 mg) or placebo, administered intrathecally in five doses over a 12-week period.

In the patients who received the highest dose of tofersen, SOD1 levels were substantially reduced in the cerebrospinal fluid (CSF). Although the trial was not sufficiently powered to demonstrate clinical efficacy, some of the treated patients also showed evidence of improvements in clinical function and muscle strength.

“We are currently studying the efficacy and safety of tofersen in a phase III study,” says Miller. “The study is enrolling a mix of fast-progressing and slow-progressing patients so we can fully understand the potential of the drug.”

In the second study, two patients with SOD1 ALS received a SOD1-targeting microRNA, delivered into the CSF via an adeno-associated virus (AAV) vector. “A potential advantage of AAV-microRNA over ASOs is the duration of action,” explains corresponding author Robert Brown. “ASOs have to be administered a few times a year, whereas in principle a single AAV-microRNA treatment should persist for years.”

Like the other trial, this study was not designed to demonstrate efficacy. However, one of the patients showed apparent preservation of strength in one leg. Post-mortem spinal cord tissue from this patient contained lower-than-average SOD1 levels. In both patients, the treatment provoked an immune response, which could be dampened with immunosuppressive drugs.

“In the patients who received the highest dose of tofersen, SOD1 levels were substantially reduced in the cerebrospinal fluid”

“We are now planning a larger trial in ~30 patients,” says Brown. “We are also likely to incorporate a version of our immunosuppression protocol into other AAV trials.”


Original articles

  1. Miller, T. et al. Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 383, 109–119 (2020)

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  2. Mueller, C. et al. SOD1 suppression with adeno-associated virus and microRNA in familial ALS. N. Engl. J. Med. 383, 151–158 (2020)

    CAS  Article  Google Scholar 

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Correspondence to Heather Wood.

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Wood, H. Moving towards genomic therapy for amyotrophic lateral sclerosis. Nat Rev Neurol 16, 460 (2020).

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