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Team Successfully Targets Common Mutation in Lou Gehrig’s Disease, Frontotemporal Dementia

By Eric Sauter

An international team led by scientists from the Florida campuses of The Scripps Research Institute (TSRI) and the Mayo Clinic have for the first time successfully designed a therapeutic strategy targeting a specific genetic mutation that causes a common form of amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig’s disease, as well a type of frontotemporal dementia (FTD).

The scientists developed small-molecule drug candidates and showed they interfere with the synthesis of an abnormal protein that plays a key role in causing both diseases. The team also developed biomarkers that can test the efficacy of this and other therapies.

The study, led by Professor Matthew Disney of TSRI and Professor of Neuroscience Leonard Petrucelli of the Mayo Clinic, was published online ahead of print August 14, 2014 in the journal Neuron.

“Our small molecules target a genetic defect that is by far the most major cause of familial ALS, and if you have this defect you are assured of getting ALS or FTD,” Disney said. “Our findings show for the first time that targeting this mutation with a small-molecule drug candidate can inhibit toxic protein translation—and establishes that it could be possible to treat a large number of these patients, but this is just the start of these studies and additional investigations need to be done.”

Currently, ALS is usually fatal two to five years after diagnosis, and there is no effective treatment for FTD, a neurodegenerative disease that destroys neurons in the frontal lobes of the brain.

Toxic Buildup

The mutation that can cause both diseases affects a gene known as C90RF72 and involves a repeat expansion, a longer than usual repetitive genetic sequence. This results in abnormal strands of RNA and the production of toxic “c9RAN proteins.”

Disney and his Scripps Florida colleagues initially designed three small-molecule drug candidates that decreased RNA translation or production of these toxic proteins in cell culture. The Mayo team developed the patient-derived cell models to test the compounds in and the biomarker to assess compound activity. Both teams then worked together to show that the lead agent’s mode of action was targeting the toxic RNA, binding to and blocking the toxic RNA’s ability to interact with other key proteins.

Two of the compounds significantly decreased levels of the toxic protein. Using a series of increasing dosages of the drug candidates, the scientists found that the highest dosage of one reduced the toxic protein by nearly 50 percent.

The scientists also discovered that c9RAN proteins produced by the abnormal RNA can be measured in the spinal fluid of ALS patients. They are now evaluating whether these proteins are also present in spinal fluid of patients diagnosed with FTD.

“A decrease in the levels of toxic proteins in cerebrospinal fluid in response to treatment would demonstrate the drug is working,” Petrucelli said. “While additional studies must be done, this finding suggests that these proteins may provide a direct means to measure a patient’s response to experimental drugs that target abnormal RNA.”

Toxic proteins found in spinal fluid could also become an enrollment tool in human clinical trials, added Disney, who was enthusiastic about the collaboration with the Mayo Clinic and the larger team. “Our collective biological and chemical expertise made this research possible,” he said. “This is just the beginning of what we can do together.”

The first authors of the study, “Discovery of a Biomarker and Lead Small Molecules to Target r(GGGGCC)-Associated Defects in c9FTD/ALS,” are Zhaoming Su of TSRI and Yongjie Zhang,  Tania F. Gendron and Peter O. Bauer of the Mayo Clinic.

Other authors include Wang-Yong Yang and Erik Fostvedt of TSRI; Jeannie Chew, Karen Jansen-West, Veronique V. Belzil, Pamela Desaro, Amelia Johnston, Karen Overstreet, Bradley F. Boeve, Dennis Dickson, Rosa Rademakers and Kevin B. Boylan of the Mayo Clinic; Mary Kay Floeter of the National Institute of Neurological Disorders and Stroke; Bryan J. Traynor of the National Institute on Aging; Claudia Morelli of the IRCCS Instituto Auxologico Italiano, Milan, Italy; Antonia Ratti and Vincenzo Silani of the IRCCS Instituto Auxologico Italiano, Milan, Italy and the Universita degli Studi di Milano, Milan, Italy; and Robert H. Brown and Jeffrey D. Rothstein of Johns Hopkins University. For additional information on the study, see

The work was supported the National Institute on Aging of the National Institutes of Health (grants R01GM097455, R01AG026251 and P50AG016574); National Institute of Neurological Disorders and Stroke (grants R21NS074121, R21NS079807, R21NS084528, R01NS088689, R01NS063964, R01NS077402 and R01NS050557); the American Recovery and Reinvestment Act of 2009 (awards RC2-NS070-342 and P01NS084974); National Institute of Environmental Health Services (grant R01ES20395); Department of Defense (ALSRP AL130125); Mayo Clinic Foundation; Mayo Clinic Center for Regenerative Medicine; Mayo Clinic Center for Individualized Medicine; ALS Association; Alzheimer's Association; Robert Packard Center for ALS Research at Johns Hopkins; Target ALS; Project ALS; Angel Fund; the Italian Ministry of Health (RF-2009-1473856) and the European Commission.

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“Our findings show for the first time that targeting this mutation with a small-molecule drug candidate can inhibit toxic protein translation—and establishes that it could be possible to treat a large number of these patients,” says TSRI Professor Matthew Disney. (Photo by James McEntee.)


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