CuATSM efficacy is independently replicated in a SOD1 mouse model of ALS while unmetallated ATSM therapy fails to reveal benefits

Abstract

A copper chelator known as diacetylbis(N(4)-methylthiosemicarbazonato) copper II (CuATSM), has been reported to be efficacious in multiple transgenic SOD1 models of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting motor neurons. Here we report that we also observed CuATSM efficacy on disease onset and progression in a standardized litter-matched and gender-balanced efficacy study using B6SJL-SOD1G93A/1Gur mice. We also report improved survival trends with CuATSM treatment. In addition, we report a lack of efficacy by unmetallated ATSM in the same model using the same standardized study design. These results add to existing evidence supporting an efficacious role for copper delivery using chaperone molecules in mouse models of ALS.

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

“…To this end, the ALS Therapy Development Institute has independently assessed prior reports of pre-clinical efficacy in mutant SOD1 mice. To date, the copper-containing compound Cu II (atsm) remains as the first and only drug candidate that the ALS Therapy Development Institute has been able to validate 6 . This provides strong support for Cu II (atsm), but validation of pre-clinical studies involving mutant SOD1 models does not address a remaining significant challenge in ALS drug development, namely, that only ~2% of ALS cases in the clinic are caused by SOD1 mutations.…”

“…Delivery of copper from Cu II (atsm) to cuproenzymes unsatiated for their natural copper requirement has been demonstrated in mutant SOD1 mice 3,5 . In these animals, the treatment also protects motor neurones in the CNS, mitigates associated deterioration of motor function, and improves overall survival [1][2][3][4][5][6][7] .…”

“…The orally bioavailable and blood-brain barrier penetrant copper compound diacetyl-bis(4-methylthiosemicarbazonato)copper II [Cu II (atsm)] is one of the most robustly tested and corroborated candidate drugs ever developed for the neurodegenerative condition of ALS, a fatal and rapidly progressive disease that selectively destroys motor neurones in the central nervous system (CNS). Pre-clinical studies involving mouse models of the disease show that oral treatment with Cu II (atsm) protects motor neurones in the spinal cord, mitigates the motor symptoms of neuronal decline, and extends survival [1][2][3][4][5][6][7] . These outcomes include mitigation of disease progression when the treatment commences after symptom onset 2 .…”

ALSUntangled 43: copper

“…First, animals co-expressing human ''copper chaperone for SOD1'' (CCS) have copper deficient mutant SOD1 and markedly accelerated disease progression (15). Second, treatment with CuATSM, which specifically releases copper into cells that have a defective electron transport chain, slows mouse disease progression (3,(16)(17)(18)(19). Finally, treatment with chelators that lower spinal cord copper levels can also slow mouse disease progression (9).…”

“…We found several studies evaluating the effect of CuATSM on mutant SOD1 mice with and without CCS coexpression (3,(16)(17)(18)(19). These are summarized in Table 3.…”