Research Highlights

MOTOR NEURON DISEASE the CSF via an adeno-associated​ virus (AAV) vector. “A potential advantage of AAV-​microRNA over ASOs is Moving towards genomic therapy the duration of action,” explains corresponding author Robert Brown. “ASOs have to be administered a few for­ amy­ otrophic­ lateral sclerosis times a year, whereas in principle a Superoxide dismutase 1 (SOD1) gene course. The participants were single AAV-​microRNA treatment mutations account for up to 20% of randomly assigned to tofersen should persist for years.” cases of familial amyotrophic lateral (20, 40, 60 or 100 mg) or placebo, Like the other trial, this study sclerosis (ALS), and this gene could administered intrathecally in five was not designed to demonstrate represent an important therapeutic doses over a 12-week​ period. efficacy. However, one of the patients target. Two new reports in The New In the patients who received the showed apparent preservation of England Journal of Medicine provide highest dose of tofersen, SOD1 levels strength in one leg. Post-mortem​ early indications that knockdown were substantially reduced in the cere­ spinal cord tissue from this patient of SOD1 expression is feasible and brospinal fluid (CSF). Although the contained lower-than-​ average​ SOD1 levels. In both patients, the treatment warrants further exploration in trial was not sufficiently powered to In the patients people with SOD1 ALS. demonstrate clinical efficacy, some provoked an immune response, The first study used the antisense of the treated patients also showed who received which could be dampened with oligonucleotide (ASO) tofersen evidence of improvements in clinical the highest immunosuppressive drugs. to target SOD1. “ASOs bind to the function and muscle strength. “We are now planning a larger dose of tofer­ trial in ~30 patients,” says Brown. target mRNA and activate RNAse H, “We are currently studying sen, SOD1 which degrades the mRNA,” explains the efficacy and safety of tofersen “We are also likely to incorporate a lead author Timothy Miller. “As in a phase III study,” says Miller. levels were version of our immunosuppression mutations in SOD1 cause a toxic “The study is enrolling a mix of substantially protocol into other AAV trials.” Heather Wood gain of function, lowering the levels fast-​progressing and slow-​progressing reduced in the of SOD1 protein is predicted to patients so we can fully understand Original articles Miller, T. et al. Phase 1–2 cerebrospinal trial of antisense oligonucleotide tofersen for be therapeutic.” the potential of the drug.” SOD1 ALS. N. Engl. J. Med. 383, 109–119 (2020) | The phase I/II trial included In the second study, two patients fluid Mueller, C. et al. SOD1 suppression with adeno- 50 patients with SOD1 ALS, 48 of with SOD1 ALS received a SOD1- ​associated virus and microRNA in familial ALS. N. Engl. J. Med. 383, 151–158 (2020) whom completed the treatment ​targeting microRNA, delivered into

PARKINSON DISEASE Regular use of NSAIDs was more common among asymptomatic carriers of LRRK2 variants than among symptomatic carriers. Regression Aspirin and ibuprofen could lower analysis indicated that regular NSAID use is associated with a lower risk of PD risk of LRRK2 Parkinson disease among people with LRRK2 mutations. The association was true for risk variants Regular use of non-steroidal​ anti- are also associated with an increased as well as pathogenic variants. ​inflammatory drugs (NSAIDs) might risk of PD. LRRK2 encodes leucine-rich​ “Our results support the hypothesis reduce the penetrance of LRRK2 Anti-​ repeat kinase 2, which is expressed in that aspirin and ibuprofen can reduce the mutations associated with Parkinson immune cells and influences inflamma- risk of PD manifestation among LRRK2 disease (PD), according to new inflammatory tory pathways. This role in inflammation carriers,” says lead author Marta San research. The findings raise the drugs may be provided the basis for investigating Luciano. “Anti-inflammatory​ drugs possibility of a simple disease-​ useful the effects of NSAIDs in people with may be useful as disease-modifying​ modifying treatment for people LRRK2 mutations. treatments in LRRK2-PD,​ and the with LRRK2 variants. as disease-​ The study involved members of two ability to identify an at-risk​ population Inflammation is thought to be involved modifying international cohorts: the Parkinson’s makes interventions in this subgroup in the pathogenesis of PD, and use of treatments Disease Genetic and Environmental particularly feasible. However, these NSAIDs, such as aspirin and ibuprofen, Modifiers cohort, and the Michael J. findings need to be replicated in other has previously been associated with in LRRK2-​PD Fox Foundation LRRK2 Cohort cohorts and in longitudinal studies, a lower risk of PD. In the new study, Consortium. In total, 577 individuals which is our planned next step.” the researchers investigated this with pathogenic or risk variants in Ian Fyfe association specifically among people LRRK2 were included — 259 had PD and with LRRK2 mutations. 318 were asymptomatic. Participants Original article San Luciano, M. et al. Autosomal dominant mutations in were asked whether they had ever taken Nonsteroidal anti-inflammatory​ use and LRRK2 Parkinson’s disease penetrance. Mov. Disord. LRRK2 are the most common cause of ibuprofen-based​ medication, aspirin or https://doi.org/10.1002/mds.28189 (2020) Mendelian PD, though the penetrance other anti-​inflammatory medications Related article Tolosa, E. et al. LRRK2 in of these mutations is low at ~30% at regularly, defined as two or more pills Parkinson disease: challenges of clinical trials. Nat. Rev. Neurol. 16, 97–107 (2020) age 80 years. Other variants in LRRK2 weekly for >6 months.

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