CuATSM has repeatedly demonstrated to be therapeutically effective in SOD1 mouse models of
amyotrophic lateral sclerosis (ALS), leading to current clinical trials.
CuATSM acts to stabilize ALS-associated mutant
SOD1 protein by supplying
copper. However, in vitro work has demonstrated that
CuATSM is only therapeutic for wild-type-like SOD1 mutants, not
metal-binding-region mutants, suggesting that
CuATSM may have genotype-specific effects. Furthermore, relatively high doses of
CuATSM have been shown to produce adverse events in humans and mice. Here, we investigated the genotype-specific therapeutic window of
CuATSM. NSC-34 cells transiently expressing
copper-binding or non-binding mutations of SOD1 were treated with a broad range of
CuATSM concentrations and examined for survival via time-lapse microscopy. Determination of the no-observed-adverse-effect level and the LC50 suggest that
CuATSM-associated toxicity is dependent on the amount of
copper-depleted SOD1 available as well as the mutant's ability to bind
copper. Our results suggest that the particular variant of SOD1 mutant is crucial in not only determining the level of efficacy achieved but also potential adverse events.