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.