Design of new clinical trials
The genetic background of ALS patients has not been taken into consideration when designing clinical trials, except of those trials which involved oligonucleotide drugs that by default target mutated genes, thus DNA analysis is indispensably required for patient selection. Specifically, the clinical trial NCT02623688 with the antisense drug targeting SOD1 tofersen (BIIB067) enrolls only patients with confirmed SOD1 mutations, while the NCT03626012 that involves the BIIB078 targeting C9ORF72 will enroll only C9ORF72 -ALS patients. However, few recent clinical trials with synthetic drug compounds have been designed to enroll ALS patients of a specific genetic background. Arimoclomol (XIX ) was found to improve muscle strength and prolong survival of Tg-SOD1G93A mice by increasing the expression of heat shock protein 70 (Kalmar et al., 2008; Kieran et al., 2004). The clinical trial NCT00706147 with arimoclomol included only patients with confirmed SOD1 mutations. Arimoclomol was safe and well-tolerated and further studies are needed to evaluate the therapeutic benefit (Benatar et al., 2018). In the same context, a clinical trial with pyrimethamine (XLII ) for FALS with SOD1 mutations to determine the safety and tolerability was performed (NCT01083667). Further, a metformin (XLIII ) clinical trial for treatment ofC9ORF72 ALS patients (NCT04220021) is now recruiting patients. This was based on the fact that although metformin has no beneficial effect in the phenotype of Tg-SOD1G93A mice (Kaneb et al., 2011), in C9-ALS/FTD mice it mitigated disease symptoms (Zu et al., 2020).
Colchicine - An example of genetic analysis to exclude FALS patients. Colchicine is an antiinflammatory drug that can also induce the expression of heat shock protein B8 (HSPB8) that enhances autophagy to remove TDP-43 of SOD1 misfolded proteins or C9ORF72 -related aggregated poly-dipeptides (Mandrioli et al., 2019; Crippa et al., 2016). An ongoing clinical trial for SALS patients (NCT03693781) excludes patients with mutations in SOD1 , TDP-43 ,FUS and C9ORF72 (Mandrioli et al., 2019).
Retrospective analysis of outcomes of clinical trials. These studies could reveal relations between chemical treatment and genetic background. In some new clinical trials, ALS patients are screened for certain mutations by DNA sequencing. In certain clinical trials, patients have provided blood samples for future DNA analysis that could be exploited in retrospective studies. Creatine is a representative example. Initially creatine administration to ALS patients did not show any improvement of clinical symptoms (Groeneveld et al., 2003). However,post hoc analysis of clinical data and genetic background of patients showed that ALS patients with A/A and A/C polymorphisms inMOBP gene will benefit for creatine treatment (Van Eijk et al., 2019). In the same direction, a meta-analysis of clinical trials that used lithium carbonate in ALS showed that lithium carbonate increased the 12-month survival probability from 40% to 70% in patients that carry the C/C polymorphism in UNC13A , while no effect inC9ORF72 carriers (Van Eijk et al., 2017).