Amyotrophic Lateral Sclerosis
Development of Copper ATSM as a Therapeutic for SOD-Familial and Sporadic ALS
Posted March 3, 2016
Joseph Beckman, Ph.D., Oregon State University
ALS is a progressive neurodegenerative disease that affects motor neurons in the brain and spinal cord. Those with ALS lose the ability to initiate and control muscle movement, typically leading to total paralysis and death within two to five years of diagnosis. There is currently no cure, and the only treatment approved by the U.S. Food and Drug Administration (FDA), riluzole, only modestly extends survival.
Dr. Joe Beckman and his team at Oregon State University have been investigating the role of copper in the pathophysiology ALS. Mouse and rat models of ALS produced by overexpression of mutant copper, zinc superoxide dismutase (Cu,Zn SOD) recapitulate the human disease with higher fidelity than other models. Overexpression of human SOD in transgenic mice is known to induce widespread changes in copper homeostasis in the spinal cord. The basis for these changes likely results from the large demand created for copper by the accumulation of copper-deficient, zinc-bound SOD in spinal cord. Because zinc strongly stabilizes unfolded SOD protein, zinc-containing SOD accumulates in the spinal cord awaiting copper from the Copper-Chaperone-for-SOD (CCS) to complete its maturation to Cu,Zn SOD. However, it has been shown that overexpression of human CCS causes mice co-expressing mutant SOD (SODxCCS) to die shortly after birth. Understanding why CCS accelerates toxicity is important because ALS patients express human CCS in a much higher ratio compared to the ratio expressed in transgenic mice. With support from an FY14 ALSRP Therapeutic Development Award, Dr. Beckman is exploring overexpression of CCS along with an increase in the amount of available copper to see if this accelerates the maturation of SOD to the fully functional Cu,Zn SOD.
Dr. Beckman proposes that the intracellular copper complex CuATSM might be able to selectively provide copper to mutant SOD neurons in the spinal cord. CuATSM is already used as an imaging agent to identify certain tumors in humans, has low toxicity, and has been shown to penetrate the blood-brain barrier of ALS patients. Beginning with a structural lead of CuATSM, shown to reduce toxicity while increasing maturation of SOD in vivo, Dr. Beckman is further optimizing the structure of CuATSM and delivery in the mouse under the ALSRP award. He expects completion of this project will result in a CuATSM derivative that maximizes survival and the successful development of essential data needed by the FDA for Phase I trials to determine safety and dosage. He proposes that CuATSM could be a treatment for both SOD-familial as well as for sporadic ALS patients.
While the ALSRP award continues to support pre-IND studies preparing CuATSM for FDA approval, the initial success in the ALS mouse model has quickly led to more advanced development. The ALS Association is supporting studies in dogs and an early clinical trial of CuATSM in ALS patients is anticipated to begin in Australia in April 2016. While this copper enhancing therapy shows promise, it is important to know that oral copper supplements do not effectively reach the central nervous system and therefore provide little benefit. Furthermore, CuATSM is remarkably safe in mice and rats, but humans and large mammals in general handle copper differently. And too much copper is toxic. The safe limits for using copper supplements are described at http://lpi.oregonstate.edu/mic/minerals/copper.
Williams JR, Trias E, Beilby PR, et al. 2016 Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD. Neurobiology of Disease 89:1-9.
Public and Technical Abstracts: Development of Copper ATSM as a Therapeutic for SOD-Familial and Sporadic ALS
Last updated Monday, January 3, 2022