SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS
Summary by Ben Hall, PhD student, the University of Sheffield
SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS.
9 July 2020
Amyotrophic lateral sclerosis (ALS) is a complex disease, meaning that therapies for its treatment are few and far between. In a healthy individual, SOD1 is a gene that provides a template for the protein superoxide dismutase. One of the leading causes of ALS is a mutation in the SOD1 gene, which has been widely studied in the search for effective treatments. Mutated SOD1 is thought to give the protein toxic properties that lead to the development of ALS. Researchers believe they may now have a method that could be used to supress expression of mutant SOD1 in people with ALS (Mueller et al., 2020).
The therapy involves a spinal injection of a virus known as AAV-mir-SOD1, that is able to suppress expression of the SOD1 gene, thus reducing expression of the mutated SOD1 protein in the patient. Two patients, Patient 1 and Patient 2, with ALS caused by a mutation in SOD1 were studied. Each patient was assessed for levels of SOD1 expression, ALSFRSR score (a measure of normal function of a patient, which ordinarily declines over the course of disease), muscle strength and lung function.
Injection of AAV-mir-SOD1 appeared to decrease expression of SOD1 in certain areas of the spinal cord of Patient 1 but not Patient 2, whilst neither patient showed any significant improvement in terms of the progression of the disease. Patient 1 also developed a neurological disease, caused by the injection, leading to Patient 2 being pre-treated with drugs that counteracted this side-effect.
Though these results may not initially seem positive, the aim of the study was not to only test the efficacy, but to also investigate the safety of this potentially ground-breaking treatment, which was demonstrated in this study. Mueller et al. (2020) show patients may eventually only require a single injection to permanently alter the course of the disease for the better.
Another paper published within the same week in the New England Journal of Medicine shows similar findings in a drug, known as Torfsen, that was shown to actively be able to reduce the expression of the SOD1 protein in ALS patients (Miller et al., 2020). These findings combined therefore represent a huge leap forward in the journey towards effective ALS therapies.
Mueller C, Berry JD, McKenna-Yasek DM, Gernoux G, Owegi MA, Pothier LM, Douthwright CL, Gelevski D, Luppino SD, Blackwood M and Wightman NS, 2020. New England Journal of Medicine, 383(2), pp.151-158.
Mueller C, Berry JD, McKenna-Yasek DM, Gernoux G, Owegi MA, Pothier LM, Douthwright CL, Gelevski D, Luppino SD, Blackwood M and Wightman NS, 2020.
SOD1 Suppression with Adeno-Associated Virus and MicroRNA in Familial ALS. New England Journal of Medicine, 383(2), pp.151-158.
Miller T, Cudkowicz M, Shaw PJ, Andersen PM, Atassi N, Bucelli RC, Genge A, Glass J, Ladha S, Ludolph AL and Maragakis NJ, 2020. Phase 1–2 trial of antisenseoligonucleotide tofersen for SOD1 ALS. New England Journal of Medicine, 383(2), pp.109-119.