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To date, more than 20 different genes have been discovered linked to the development of amyotrophic lateral sclerosis (ALS), with C9ORF72, TARDBP, SOD1 and FUS being the most prevalent.1 Since the discovery of the SOD1 mutation in 1993—the first gene associated with the disease—models based on this genetic mutation have made a significant contribution to understanding ALS pathogenesis. So far, more than 180 SOD1 mutations have been described, further contributing to ALS heterogeneity through expression as different clinical phenotypes. However, despite these advances in genetic understanding, ALS remains a universally fatal neurodegenerative disease, typically resulting in death within 2–3 years.2 ,3 The clinical, pathological and genetic heterogeneity of ALS has made it difficult to develop therapeutic targets and neuroprotective approaches.4 Until now, the only neuroprotective treatment capable of modifying the disease course is riluzole, a glutamate release inhibitor and sodium channel modulator that provides a modest survival benefit of 3–6 months.
In their JNNP manuscript, Bali and colleagues5 contribute to expanding knowledge about the natural history of familial ALS related to SOD1 mutations (ALSSOD1). With the objective to update the natural history of ALSSOD1, the authors performed a cohort study of 175 patients with ALSSOD1 from 15 North American centres. Patients with ALSSOD1 were analysed in terms of age of disease onset, survival, ALS functional rating scale (ALSFRS) and respiratory function. Given that AV4 represents the most common SOD1 mutation reported in the North American population, the authors subdivided the ALSSOD1 cohort based on this mutation (SOD1AV4 and SOD1Non-AV4, respectively). In terms of findings, the authors reported a mean age of onset of 49.7 years and median survival of 2.7 years across all patients with ALSSOD1, with a significant decrease in survival in SOD1AV4 compared with SOD1Non-AV4 patients (1.2 vs 6.8 years). In addition, there was a significant increase in ALSFRS rate of decline in SOD1AV4 patients, leading the authors to conclude that SOD1AV4 was an aggressive mutation. This characterisation of the natural history of ALSSOD1 will be highly relevant for the design of future clinical trials, particularly in terms of sample size estimation.
Unfortunately, negative clinical trial outcomes remain pervasive across the realm of ALS, despite consideration of an extensive range of potential neuroprotective strategies including antioxidants, vitamins, mitochondrial modulators, immunotherapy and stem cell transplantation. Studies targeting specific pathological processes, such as the use of antisense oligonucleotides in carriers with a specific ALS mutation, have also proved disappointing. While the clinical, pathological and genetic characterisation of ALS has certainly improved, the translation into effective treatments for patients with ALS has been elusive. The lack of translational success from SOD1 models likely reflects multiple issues, but perhaps must critically relate to the lack of accumulation of TDP-43 in neuronal and glial cells, the pathological signature common to most forms of ALS. In contrast, motor neurone degeneration secondary to SOD1 mutations seems to be the product of a toxic gain of function in the misfolded mutant SOD1 protein. Interestingly, in sporadic ALS, recent evidence suggests that misfolded wild-type SOD1 protein may additionally be involved in pathogenesis.6 The generation of this misfolded wild-type SOD1 protein, with resultant toxic conformation, may be induced by non-genetic modifications including oxidation, metal depletion, and potentially through the presence of TDP-43 and FUS, as suggested by recent experimental data.7
Perhaps, however, the tide is now starting to turn. Specifically, identification of this toxic wild-type misfolded SOD1 protein may strengthen the feasibility of a targeted therapeutic approach, not only for familial ALS but also for sporadic patients. In this regard, a novel ALS treatment based around the concept of copper supplementation has recently been suggested.8 Copper is a key cofactor for the function of the normal SOD1 protein, and low levels have been associated with the development of the misfolded protein. In the SOD1G93A transgenic mouse model of ALS, the administration of a normal copper compound (CuATSM, a positron emission tomography imaging contrast agent capable of transporting copper into the brain) extended the lives of rodent models by 18 months. In addition, restoring copper with CuATSM treatment essentially ‘rescued’ neurones from their symptomatic stage. The effect of CuATSM in patients with ALS and its potential for modulating wild-type SOD1 in sporadic ALS remain to be tested, with phase I clinical trials on the immediate horizon.
As such, understanding the genetic and clinical features of ALSSOD1 may yet become more therapeutically relevant to sporadic ALS, in addition to assisting the design of future clinical trials. Advancing our knowledge with information from subtype-specific ALS subgroup analyses may eventually enable the development of individualised therapies, laying the foundation for a future of personalised medicine.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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