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AriSLA - The Foundation for research on ALS - has been set up to make ALS research investments more effective and efficient, to speed up the clinical research impact e and to provide patients with better care, improved conditions and life expectancy. Its aim is to boost Italian excellencies in basic, clinical and technological research. The Foundation founders are Fondazione Cariplo, Fondazione Telethon, Fondazione Vialli and Mauro and AISLA.

 

 

Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in ALS mouse model

 

In a recent paper published in January in Neurobiology of Disease online, Dr. Joseph Beckman of Oregon State University, reported results obtained by his group by treating Cu/Zn superoxide dismutase1 (SOD1) G93A mice with CuATSM, a copper chelator that can carry the metal into the brain and spinal cord.

 

The group have previously shown that CuATSM can deliver copper to SOD in SODG37R mice (J. Neurosci. 2014 Jun 4;34(23):8021-31. Oral treatment with Cu(II)(ATMS) increases mutant SOD1 in vivo but protects motor neurons and improves the phenotype of a transgenic mouse model of amyotrophic lateral sclerosis. Roberts BR et al.), and the same chelator agent has also shown therapeutic promise in Parkinson's disease (results presented at International Conference on Alzheimer's & Parkinson's Diseases 2011).

The toxic gain-of-function of the mutated SOD1 protein, involved in a subgroup of familial ALS patient, "appears to involve partially unfolded intermediates of SOD, which often lack the metal cofactors critical for stabilization" - as reported in the paper - causing its aggregation.

 

Starting from the analysis of the reason why human Copper-Chaperone-for-SOD (CCS) accelerates toxicity of SOD1G93A mice, researchers thought that CuATSM could be a promising therapeutics for ALS, hypothesizing that co-expression of CCS created copper deficiency in spinal cord. CuATSM is used as a PET-imaging agent for hypoxic tumors in humans, has low toxicity, and penetrates the blood-brain barrier of ALS patients in minutes.

In the paper they showed that treatment with CuATSM had a particularly strong effect in mouse overexpressing both human mutant SOD1 and its copper chaperone CCS, but also it was able to extend the life of a more standard ALS model carrying only the SOD1 transgene.

Moreover, 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 three months. Restoring CuATSM treatment rescued these mice after they became symptomatic.

 

Beckman and colleagues believe the drug works by supplying copper not only to SOD1, but also to cytochrome oxidase c (COX), a respiratory enzyme that loses its copper to SOD1 in the mSOD1xCCS mice.

In the paper conclusions they stated - "Because copper uptake in the CNS is highly regulated and its turnover is extremely slow, copper supplements cannot replace CuATSM for treating ALS. Copper supplements can damage the liver and are generally toxic at high dosages. CuATSM offers a safe delivery vehicle to bypass the distribution system naturally limiting copper transport into the CNS, providing sufficient copper for CCS to complete the maturation of Cu,Zn SOD while avoiding the toxicity of high dietary copper intake".

The Australian company Collaborative Medicinal Development plans to start a Phase 1 safety study of CuATSM in people with ALS this year. Senior author Joseph Beckman of Oregon State University in Corvallis advises the company.

 

More detailed information can be found at http://www.researchals.org/page/4746/15269/

 

Reference:

Williams JR, Trias E, Beilby PR, Lopez NI, Labut EM, Bradford CS, Roberts BR, McAllum EJ, Crouch PJ, Rhoads TW, Pereira C, Son M, Elliott JL, Franco MC, Estévez AG, Barbeito L, Beckman JS. Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SOD(G93A) mice co-expressing the Copper-Chaperone-for-SODNeurobiol Dis. 2016 Jan 27;89:1-9. [PubMed].

 

 

 

 




     
     
     
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