Disrupted copper availability in sporadic ALS: Implications for Cu^II(atsm) as a treatment option

Abstract

Objective: The copper compound Cu II (atsm) is in phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Cu II (atsm) consistently and reproducibly ameliorates neurodegeneration in mutant SOD1 mouse models of ALS where its neuroprotective activity has been ascribed in part to improving availability of copper to essential cuproenzymes. However, SOD1 mutations cause only ~2% of ALS cases with most cases being of unknown aetiology. Therapeutic pertinence of Cu II (atsm) to sporadic ALS is therefore unclear. Methods:We assayed post-mortem spinal cord tissue from sporadic cases of ALS for the anatomical and biochemical distribution of copper, the expression of genes involved in copper handling, and the activities of cuproenzymes. Results:The natural distribution of copper is disrupted in sporadic ALS. The ALS-affected tissue has a molecular signature consistent with an unsatiated requirement for copper and cuproenzyme activity is affected. Copper levels are decreased in the ventral grey matter, the primary anatomical site of neuronal loss in ALS.Interpretation: Mice expressing mutant SOD1 recapitulate salient features of ALS. The unsatiated requirement for copper that is evident in these mice is a biochemical target for Cu II (atsm). Evidences provided here for disrupted copper bioavailability in human cases of sporadic ALS indicate that a therapeutic mechanism for Cu II (atsm) involving copper bioavailability is pertinent to sporadic cases of ALS, and not just those involving mutant SOD1.

Copper bis(thiosemicarbazone) complexes modulate P‐glycoprotein expression and function in human brain microvascular endothelial cells

“…The mechanism by which these compounds cross cell membranes, their subcellular trafficking, and how they regulate cellular responses is yet unknown. However, these BTSC compounds have immense potential as neurodegenerative therapeutics, and as diagnostic and imaging agents, with early clinical trials demonstrating promising outcomes in neurodegenerative diseases (Hilton et al, 2017; Hilton et al, 2020; Hung et al, 2012; Price et al, 2011; Southon et al, 2020; Williams et al, 2016). Therefore, while the BTSCs were used as model compounds to address the central question around whether Cu is involved in the regulation of P‐gp at the BBB, they also have clinical potential and the findings from this study could provide additional insight into mechanisms associated with their benefits observed in disease models.…”

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis

“…Phase II/III testing is in progress after successful completion of the phase I trial in ALS patients. In this assay involving post-mortem spinal cord tissue from sALS, it is considered that Cu II (atsm) can be beneficial to sALS, enabling copper to transfer from the complex into mutant SOD1 [ 89 ].…”

Cells Overexpressing ALS-Associated SOD1 Variants Are Differentially Susceptible to CuATSM-Associated Toxicity

“…17,42−44 Furthermore, disrupted copper bioavailability has been reported in sALS cases. 45 Ultimately, using CuATSM at a lower, or individualized, concentration in combination with other therapies, 14,15 such as ebselen, and considering its potential SOD1-independent mechanisms, there is therapeutic potential for a larger range of fALS or sALS cases moving forward into the clinic.…”