Illawarra Health and Medical Research Institute, Wollongong, NSW 2522, Australia.
Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW 2522, Australia.
ACS Chem Neurosci. 2022 Aug 17;13(16):2371-2379. doi: 10.1021/acschemneuro.2c00253. Epub 2022 Jul 28.
CuATSM has repeatedly demonstrated to be therapeutically effective in 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, 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 LC 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.
CuATSM 在肌萎缩侧索硬化症（ALS）的小鼠模型中已被证明具有治疗效果，目前正在进行临床试验。CuATSM 通过提供铜来稳定与 ALS 相关的突变 SOD1 蛋白。然而，研究表明，CuATSM 仅对野生型样 SOD1 突变体具有治疗作用，而对金属结合区域突变体无效，这表明 CuATSM 可能具有特定于基因型的作用。此外，相对较高剂量的 CuATSM 已被证明会在人类和小鼠中产生不良反应。在这里，我们研究了 CuATSM 的基因型特异性治疗窗口。用广泛浓度的 CuATSM 处理瞬时表达铜结合或非结合突变 SOD1 的 NSC-34 细胞，并通过延时显微镜检查细胞存活情况。无观察到不良反应水平和 LC 的测定表明，CuATSM 相关的毒性取决于可用的铜耗竭 SOD1 的量以及突变体结合铜的能力。我们的结果表明，SOD1 突变体的特定变体不仅决定了达到的疗效水平，而且还决定了潜在的不良反应。
