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Antisense Treatment Shows Hope for Genetic Form of ALS

ALTHOUGH the cause of amyotrophic lateral sclerosis (ALS) is unknown, in 10% of cases it due to genetic mutations, many of which can be single nucleotide polymorphism mutations in the superoxide dismutase 1 (SOD1) gene. A new antisense oligonucleotide (tofersen) that targets this mutated gene to reduce the concentration of mutated protein has shown promise in an initial safety trial.

A study to examine the safety, tolerability, and exploration of dosage and efficacy of the experimental antisense drug was conducted. The study consisted of 50 patients with ALS caused by the SOD1 mutation. They received five doses of either 20, 40, 60, or 100 mg of the drug, or placebo, delivered via lumbar puncture or spinal tap over 3 months.

SOD1 converts metabolic waste products produced in the cell into water. Mutations in the SOD1 gene that cause ALS are thought to result in the disruption of the SOD1 protein structure, causing them to become sticky and form aggregates. These aggregates are a hallmark of ALS and it is thought that they can trap other metabolic enzymes creating a toxic environment in the cell resulting in cell death; this is one of the current theories for the death of motor neurons which causes ALS.

Reduced SOD1 protein levels in the spinal fluid were observed in 10 patients who received 100 mg of the drug compared to 12 patients on placebo. Furthermore, they scored better on tests that measure breathing capacity, muscle strength, and functionality of activities. Those on placebo experienced a 5.3-point decline in comparison to 1.1 points in those on 100 mg of the drug, where the maximum points achievable in functionality is 48. Only mild to moderate adverse events were reported, including headache, pain due to procedure, and post lumbar puncture syndrome.

Timothy Miller, Washington University School of Medicine, St Louis, Missouri, USA, and author of the original study article commented: “Lower concentrations of the protein in the spinal fluid suggest that there were also lower concentrations in the brain and spinal cord. Such reductions could lead to preservation of motor neurons and slow progression of the disease, but more study is needed to examine this further.”