The need for stratification of ALS patients
Despite uniform clinical features in patients with established ALS, it
is now understood that ALS is nothing but a homogenous disease (Swinnen
and Robberecht, 2014) and most likely quite distinct biological pathways
are involved, as also indicated by the functional versatility of the
proteins encoded by pathogenetic variants of the identified familial ALS
genes. The frequent failure of candidate compounds tested for ALS in
clinical trials, which proved effective in animal models, could be
explained by the fact that animal models represent a given ALS genotype,
while clinical trials are conducted with non-stratified, thus,
genetically heterogenous patient populations. Interrogation of the
clinical trial database
(http://clinicaltrials.gov)
against “amyotrophic lateral sclerosis” retrieved 715 hits of which
only 569 were related to ALS and the rest to SMA (spinal muscular
atrophy). Of ALS trials, 146 involved the administration of 50 different
small molecules but in only nine recent trials, patients were selected
based on their involved ALS pathogenic gene. In the era of precision
medicine, treatment decisions are guided by genetic/molecular data
according to which patients are stratified into subgroups. The following
two examples highlight the need for subgrouping ALS patients:
[1] ALS due to mercury intoxication. Incidentally, an SALS
patient was identified who suffered ALS due to mercury intoxication and
was treated with a combination of the chelator
2,3-dimercaptopropanesulfate and a-lipoic acid for mercury cleansing
that was expected to ameliorate symptoms. In fact, this case turned to
be the first reported ALS cure (Mangelsdorf et al., 2017). This is
reminiscent of the loss of metal homeostasis reported in Alzheimer
disease, for which either Zn2+ supplementation or
Fe3+/Al3+ chelation therapies have
been suggested (Adlard and Bush, 2018). Notably, metallomic analysis
revealed uranium in the CSF of 47% of ALS patients examined in a
Scandinavian study (Roos et al., 2013), suggesting that chelation
treatment could be beneficial for this subgroup.
[2] The case of Guam – How changing diet can prevent ALS.In Guam, the incidence of ALS was unexpectedly high, i.e.approximately 200/100,000, making it a rather common neurodegenerative
disease. Neurotoxin β-methylamino-L-alanine (L-BMAA) (III ), a
component of cycad seeds consumed in Guam was identified as the ALS
causing agent. Cycad seeds are consumed and bioaccumulated by flying
foxes (bats) in the island which are popular food for locals. As a
result, they intake large quantities of L-BMAA (Cox et al., 2003).
Intravenous injection of L-BMAA induces ALS-PDC disease in rats that is
accompanied by appearance of cytosolic TDP-43 aggregates (Tian et al.,
2016). The incidence of ALS-PDC is constantly declining in Guam,
following diet changes towards restricted bat consumption (Monson et
al., 2003).
These two examples successfully demonstrate how the knowledge of the
causative agent of ALS can lead to the design of successful targeted
therapies and/or prevention measures.