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.