Introduction
Amyotrophic lateral sclerosis (ALS) is a rare but rapidly progressive neurodegenerative disease with an estimated prevalence of 2:100,000. It is characterized by loss of motor neurons in the brain and spinal cord uniformly leading to death within 3-5 years from diagnosis most frequently due to respiratory paralysis (Brown and Al-Chalabi, 2017). Two ALS types can be distinguished, i.e. , familial ALS (FALS) that accounts for 5-10% of all ALS cases and sporadic ALS (SALS) that accounts for the rest. The hallmark of ALS is the abnormal accumulation of intracellular protein aggregates that vary in composition and could contain TDP-43, SOD1, FUS or various poly-dipeptides encoded by pathogenic GGGGCC expansions in the C9ORF72 gene. TDP-43 aggregates in the cytoplasm of neuronal cells are a common finding in ALS (especially SALS) patients except for patients that carry pathogenic variants in SOD1 (Blokhuis et al., 2013). Intriguingly though, pathogenic variants in >30 genes are responsible for ALS, without including disease modifier genes that significantly increase the heterogeneity of ALS (Pampalakis et al., 2019). Most commonly, mutations occur in C9ORF72 , SOD1 , TDP-43 and FUS genes underly respective FALS forms but are also found in many SALS cases (Zou et al., 2017). The underlying molecular complexity of SALS is further increased by various environmental factors (Hardiman et al., 2017) highlighted by studies of ALS-PDC (amyotrophic lateral sclerosis-parkinsonism-dementia) prevalent in the pacific island of Guam, outlined below.
Riluzole (I ) and edaravone (II ) are the only drugs approved by the FDA for treatment of ALS, nevertheless, no significant improvement of disease or quality of life of ALS patients was observed by either of these drugs (Jaiswal, 2019; Mitropoulos et al., 2018). Stem cell therapies (Goutman et al., 2019), gene therapies (Cappella et al., 2019) and vaccinations (Zhou et al., 2020), are in early stages of development, thus, not expected to enter routine clinical practice in the near future. Consequently, there is a pressing need for chemical entities with pharmacological efficacy to attenuate disease symptoms and improve quality of life of ALS victims.