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.