In 1993, a multinational collaboration of geneticists and neurologists identified the first gene that caused amyotrophic lateral sclerosis (ALS). Surprisingly, the identified gene makes a well-known antioxidant protein called copper, zinc superoxide dismutase. This raised hopes that the disease could be treated with antioxidants, but all such efforts have failed. The superoxide dismutase protein was already being tested clinically in patients to protect against stroke and heart attacks, so its potential involvement in ALS was a complete shock. Within a year of the discovery, molecular biologists had transferred the mutant human superoxide dismutase gene into mice to produce the first animal model of ALS. These mice developed a progressive paralysis beginning in the hind paws after 3 months and reach the end of life by 4 months. This experimental model recapitulates the human disease better than any other ALS model developed to date. The challenge has been that no one in two decades has discovered any therapy that extends life of these mice by more than 2 weeks.

We have found that a small copper-transporting molecule called CuATSM that can essentially stop ALS from developing in the superoxide dismutase mice. These mice develop disease if CuATSM treatment is removed, and restoring treatment can halt further progress of the disease. We have developed powerful experimental approaches that showed CuATSM works by completing the maturation of SOD through supplying copper safely to neurons in the spinal cord.

What types of ALS patients with CuATSM potentially benefit? Clearly, ALS patients who carry superoxide dismutase mutations would be the prime candidates for treatment. While the mouse model predicts this should be effective, superoxide dismutase mutations only account for 2%-7% of all ALS cases. That would treat only 60-210 of the 3,000 people thought to develop ALS each year in America. However, we expect CuATSM should not only work in patients without SOD mutations, but paradoxically might respond even better than patients carrying superoxide dismutase mutations.

What are the potential clinical applications, benefits, and risks? CuATSM is used as an imaging agent now in humans and has undergone safety testing at low dosages for the Food and Drug Administration (FDA). It is orally active, so could be taken as a single pill per day. We have not found a toxic dosage after a year of continuous administration given twice daily in mice. However, many questions must be answered before CuATSM can be tested in ALS patients. The work supported by this award will determine how to make large amounts of CuATSM suitable for human use, how it is metabolized and how to best deliver CuATSM to humans. In addition, we will determine if small changes to the chemical structure of CuATSM can lead to a safer or more effective agent for long-term treatment of patients. If we can establish how to use CuATSM or a derivative safely for continuous use, it could be used to protect people from developing ALS who carry SOD mutations.

What is the projected time it may take to achieve a patient-related outcome? Completion of the proposed studies should lead to approval from the FDA for initial clinical studies of safety and dosage. It may be possible to know if the treatment works in patients within a year after the FDA approves an IND (Investigational New Drug) Application.

What is the likely contribution of this study in advancing the development of therapeutics for ALS? CuATSM offers a new experimental approach to turn off and on the progression of ALS in mice. This should allow further testing of other agents that could modulate the ALS disease process as its causes are unraveled. CuATSM also has great potential for restoring mitochondrial function, which has many implications for treating ALS as well as many other neurodegenerative diseases.