The ALS Association

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Drug-like Small Molecule Reduces Potentially Harmful ALS Gene Products

August 14, 2014

Washington, D.C. (August 14, 2014) — In work supported by The ALS Association, researchers have developed a drug-like molecule that reduces some of the potentially harmful products of the most common ALS-causing gene. In addition, they showed that these products could be detected in the spinal fluid of people with this genetic form of ALS, suggesting that they could serve as a biomarker for therapy designed to treat this form of the disease. The study was published in the journal Neuron.

ALS (amyotrophic lateral sclerosis), also known as Lou Gehrig’s Disease, is a progressive neurodegenerative disease that affects neurons (nerve cells) in the brain and the spinal cord. Eventually, people with ALS lose the ability to initiate and control muscle movement, which often leads to total paralysis and death within two to five years of diagnosis. There is no cure and no life-prolonging treatments for the disease. 

The research team focused on the products of the expanded C9orf72 gene, responsible for up to 40 percent of familial ALS and 6 percent of sporadic ALS, as well as many cases of frontotemporal dementia. The gene expansion causes accumulation of repeated lengths of RNA, a genetic messenger molecule. The accumulated RNA is believed to interfere with multiple cell processes, contributing to the disease. In addition, it is used by the cell to make unusual proteins called c9RAN proteins. Whether these proteins cause additional harm in the neuron is unknown.

Building on previous work in a different neurologic disease that is also due to an RNA expansion, the team tested several drug-like small molecules for their ability to reduce the accumulation of RNA and the production of c9RAN proteins. Working in cell models of ALS, they found that one, called molecule 1a, produced a dose-dependent reduction in c9RAN proteins and reduced RNA accumulation. Not every type of c9RAN protein was reduced, however, and further work will be needed to determine the significance of this partial reduction.

Finally, the team showed that c9RAN proteins could be detected in spinal fluid from people with ALS due to the C9orf72 gene expansion. This discovery should make it easier to monitor the effects of any future treatment targeting the C9orf72 gene. A reduction in c9RAN proteins would indicate the treatment was likely having the intended biochemical effect.

The research was led by Zhaoming Su, Ph.D. and Yongjie Zhang, Ph.D., of the Scripps Research Institute in Jupiter, Florida, as well as Tania Gendron, Ph.D. and Peter Bauer, Ph.D., of the Mayo Clinic in Jacksonville, Florida, under the leadership of Matthew Disney, Ph.D., of Scripps and Leonard Petrucelli, Ph.D., of the Mayo Clinic. Drs.  Su and Gendron were former Milton Safenowitz postdoctoral fellows, and Drs. Zhang, Petrucelli, Gendron and Bauer are current ALS Association grantees.

“This work is highly significant for two reasons,” said Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The Association. “First, it provides proof of principle that small molecules can have a positive effect on the gene products of this common disease-causing gene. That gives us confidence that we can develop drugs to treat this form of the disease at its source. Second, the presence of the C9RAN proteins in the spinal fluid should give us a valuable tool for measuring the effect of therapies. Developing such biomarkers has been a principle research focus of The ALS Association, and it is gratifying to see a new one emerging in this research.”

About The ALS Association
The ALS Association is the only national non-profit organization fighting Lou Gehrig’s disease on every front.  By leading the way in global research, providing assistance for people with ALS through a nationwide network of chapters, coordinating multidisciplinary care through certified clinical care centers, and fostering government partnerships, The Association builds hope and enhances quality of life while aggressively searching for new treatments and a cure.  For more information about The ALS Association, visit our website at

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