Pharmacological modulation of gene modifiers
Modifier gene alleles either exacerbate or attenuate the clinical presentation of ALS (Table 1). The identification and characterization of modifier genes is an ongoing endeavor that could provide new therapeutic options for certain ALS subgroups (Yanagi et al. 2019). Ephrin A4 (EPHA4) is a well-established ALS gene modifier (Van Hoecke et al., 2012). Loss-of-function mutations in EPHA4 associate with longer survival of ALS patients and different ALS animal models (Table 1). Thus, pharmacological inhibition of EPHA4 could provide a new way to treat ALS. In this direction, the 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2-hydroxy benzoic acid (XL ), a pharmacological inhibitor of EphA4 (Noberini et al., 2008), rescues mutant SOD1 induced axonopathy in zebrafish (Van Hoecke et al., 2012). The compound 123C4 (XLI ) is an EphA4 receptor binding agent that prolongs survival of Tg-SOD1G93A mice by 8.5 days (Wu et al., 2017). EPHA4 can be considered a “universal” ALS gene modifier since it acts as modulator for both SOD1 and TDP-43 associated ALS. However, administration of antisense oligonucleotides targeting EphA4 did not affect motor function or survival of Tg-SOD1G93A or Tg-PFN1G118V mice, although it significantly delayed (from 154 to 199 days) the onset of symptoms in Tg-PFN1G118V (Ling et al., 2018). The success of chemical targeting of EphA4 to prolong survival in animal models over oligonucleotide targeting could be related to the fact that the former study targeted both the CNS and periphery, while oligonucleotides administered icv targeted only the CNS.
Lithium carbonate (Li2CO3) increased the 12-month survival probability of ALS patients bearing the UCN13AC/C polymorphism. Thus, lithium carbonate may be used only for this patient subgroup (van Eijk et al., 2017). Another well-described ALS gene modifier is CX3CR1 (Lopez-Lopez et al., 2014). Deletion ofCx3cr1 in Tg-SOD1G93A mice reduced lifespan, increased neuronal loss and SOD1 aggregation (Liu et al., 2019).
Another ALS gene modifier with potential pharmacological application is the IL6R C allele that results in the substitution D358A in the interleukin 6 receptor. IL6R C ALS carriers have increased levels of IL6 and soluble IL6R in serum and CSF and accelerated disease progression rates (Wosiski-Kuhn et al., 2019), nevertheless, deletion ofIl6 in Tg-SOD1G93A did not alter the lifespan (Han et al., 2016). Administration of tocilizumab, a humanized monoclonal antibody against IL6R, in SALS patients displaying strong expression of inflammatory genes in peripheral blood mononuclear cells (PBMCs), attenuated clinical symptoms. In contrast, administration of tocilizumab in SALS patients with weak inflammatory gene expression upregulated the inflammatory reaction (Fiala et al., 2013). Whether anti-IL6R therapies may be more effective in IL6R C carriers with no SOD1 mutations remains to be investigated.