Copper, zinc superoxide dismutase is essential to life, but when damaged can become toxic. Credit: Photo courtesy of Oregon State University
OSU researchers have announced that they have essentially stopped the progression of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, for nearly 2 years in one type of mouse model used to study the disease – allowing the mice to approach their normal lifespan. In decades of work, no treatment can do anything but prolong human survival less than a month in ALS. This mouse model is one that may more closely resemble the human reaction to this treatment, using copper-ATSM. Researchers are moving as quickly as possible toward human clinical trials, testing first for safety and then efficacy.
ALS is known to be caused by the death and deterioration of motor neurons in the spinal cord, which in turn has been linked to mutations in copper, Zn superoxide dismutase. Copper-ATSM helps deliver copper specifically to cells with damaged mitochondria, and reaches the spinal cord where it’s needed to treat ALS. This compound has low toxicity, easily penetrates the blood-brain barrier, is already used in human medicine at much lower doses for some purposes, and is well tolerated in laboratory animals at far higher levels. Any copper not needed after use of copper-ATSM is quickly flushed out of the body.
Experts caution, however, that this approach is not as simple as taking a nutritional supplement of copper, which can be toxic at even moderate doses. Such supplements would be of no value to people with ALS, they said.
Using the new treatment, researchers were able to stop the progression of ALS in one type of transgenic mouse model, which ordinarily would die within 2 weeks without treatment. Some of these mice have survived for >650 days, 500 days longer than any previous research has been able to achieve.
In some experiments, the treatment was begun, and then withheld. These mice began to show ALS symptoms within 2 months after treatment was stopped, and would die within another month. But if treatment was resume, the mice gained weight, progression of the disease once again was stopped, and the mice lived another 6-12 months.
“We have a solid understanding of why the treatment works in the mice, and we predict it should work in both familial and possibly sporadic human patients,” Beckman said. “But we won’t know until we try.”
The advances are based on substantial scientific progress in understanding the disease processes of ALS and basic research in biochemistry. The transgenic mice used in these studies have been engineered to carry the human gene for “copper chaperone for superoxide dismutase,” or CCS gene. CCS inserts copper into superoxide dismustase, or SOD, and transgenic mice carrying these human genes die rapidly without treatment.
After years of research, scientists have developed an approach to treating ALS that’s based on bringing copper into specific cells in the spinal cord and mitochondria weakened by copper deficiency. Copper is a metal that helps to stabilize SOD, an antioxidant protein whose proper function is essential to life. But when it lacks its metal co-factors, SOD can “unfold” and become toxic, leading to the death of motor neurons.
There’s some evidence that this approach, which works in part by improving mitochondrial function, may also have value in Parkinson’s disease and other conditions, researchers said. Research is progressing on those topics as well.
The treatment is unlikely to allow significant recovery from neuronal loss already caused by ALS, the scientists said, but could slow further disease progression when started after diagnosis. It could also potentially treat carriers of SOD mutant genes that cause ALS. http://oregonstate.edu/ua/ncs/archives/2016/jan/new-therapy-halts-progression-lou-gehrig%E2%80%99s-disease-mice
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