Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD^G93A mice co-expressing the Copper-Chaperone-for-SOD protein (CCS)

Over-expression of a mutant copper, zinc (Cu,Zn)-superoxide dismutase (SOD) in the SODG93A mouse induces ALS and has become the most widely used laboratory animal model of neurodegeneration. However, no pharmaceutical agent in 20 years has extended lifespan by more than a few weeks. The Copper-Chaperone-for-SOD protein (CCS) encoded by the mouse Ccs gene completes the maturation of SOD by inserting copper.

Paradoxically, human CCS coded for by the CCS gene causes mice co-expressing mutant SODG93A to die within two weeks of birth. Authors in the present report [attached] postulated that co-expression of CCS might create copper deficiency in the spinal cord. Therefore, they treated these pups co-expressing mutant SODG93A with the PET-imaging agent CuATSM––which is known to deliver copper into the central nervous system within minutes. CuATSM prevented the early mortality of CCSxSOD mice, while markedly increasing the Cu,Zn-SOD protein in their ventral spinal cord. Remarkably, continued treatment with CuATSM extended the survival of these mice by an average of 18 months. When CuATSM treatment was stopped, these mice developed ALS-related symptoms and died within 3 months. Restoring CuATSM treatment could rescue these mice after they became symptomatic, providing a means to start and stop disease progression.

All ALS patients also express human CCS, raising the hope that familial SOD ALS patients might respond to CuATSM treatment similarly to the CCS x SODG93A mice. Clinical trials have not yet been reported but most likely are underway.

Neurobiol Dis 2o16; 89: 1–9

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