Research at Johns Hopkins has helped a team of scientists elsewhere identify and develop a compound that could directly target a genetic mutation responsible for a common familial form of amyotrophic lateral sclerosis (ALS) and a biologically related memory-robbing disease known as frontotemporal dementia (FTD).
This new chemical, announced in the Sept. 3 issue of the journal Neuron by scientists at Mayo Clinic and the Scripps Research Institute, is still years from testing on patients, Johns Hopkins experts caution. But it constitutes a hopeful advance toward treating both conditions, for which there are currently no effective therapies, says Jeffrey Rothstein, M.D., Ph.D., a neuroscientist specializing in ALS at Johns Hopkins.
Three years ago, researchers at the National Institutes of Health, Mayo Clinic and other institutions, including Johns Hopkins, discovered that more than 40 percent of patients with an inherited form of ALS and at least 10 percent of patients with the noninherited sporadic form have a mutation in a so-called C9ORF72 gene found on human chromosome 9 that is involved in toxic proliferation of protein.
The mutation also occurs very often in people with FTD, the second-most common form of dementia after Alzheimer’s disease. In the C9ORF72 gene of most people, there are up to 30 repeats of a series of six DNA letters (GGGGCC), but in people with the genetic glitch, the string can be repeated thousands of times. These extraneous repeats can lead to production of toxic RNA fragments and the C9RAN protein, which has been hypothesized to affect the function of many other proteins throughout cells.
In the Mayo-Scripps study, chemists report they have developed three different molecules with the potential to decrease production of C9RAN. Tests on nerve cells derived from patients with the mutation showed that one of the new chemicals cut the quantity of C9RAN by half at the highest dose the researchers delivered, making it a good candidate for human disease therapy.
The researchers also checked for C9RAN protein in the spinal fluid of patients at ALS clinics, including the Johns Hopkins clinic directed by Rothstein, who also directs the Brain Science Institute and Robert Packard Center for ALS Research. They found that this protein spills out of affected cells into the spinal fluid. Therefore, says Rothstein, “A spinal fluid assay would give clinicians a readout that the drug is or is not working. This offers the perfect opportunity to see if this drug can minimize the toxic protein load in patients.”
Rothstein emphasizes that before clinical trials can occur, the molecule itself needs to be more thoroughly tested, and researchers need to gather more information on the presence of C9RAN protein in patients — for example, whether concentrations of the protein vary day to day or whether they increase as the disease progresses.
However, he says, the study offers a glimpse at what could be a promising future therapy for patients with this familial form of ALS and FTD.
“The good news,” says Rothstein, “is that our colleagues at Mayo and Scripps have discovered a compound that looks pretty good at doing what it needs to do.”
ALS, sometimes known as Lou Gehrig's disease, which was named as such for the Yankee baseball great who died from it in 1941, destroys nerve cells in the brain and spinal cord that control voluntary muscle movement. About 5,600 people are diagnosed with ALS in the U.S. every year.
As nerve cells waste away or die, ALS patients lose muscle strength and ultimately the ability to move their bodies or perform any voluntary function. About 10 percent of cases are hereditary.
Other authors on the paper are Zhaoming Su, Wang-Yong Yang, Erik Fostvedt and Matthew D. Disney of the Scripps Research Institute; Yongjie Zhang, Tania F. Gendron, Peter O. Bauer, Jeannie Chew, Karen Jansen-West, Veronique V. Belzil, Pamela Desaro, Amelia Johnston, Karen Overstreet, Bradley F. Boeve, Dennis Dickson, Rosa Rademakers, Kevin B. Boylan and Leonard Petrucelli of 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, Antonia Ratti and Vincenzo Silani of IRCCS Istituto Auxologico Italiano; and Robert H. Brown of the University of Massachusetts Medical School.
This work was supported by the National Institute on Aging (grant numbers R01GM097455 and R01AG026251), the National Institute of Neurological Disorders and Stroke (grant numbers R21NS074121, R21NS079807, R21NS084528, R01NS088689, R01NS063964, R01NS077402, R01NS050557, RC2-NS070-342 and P01NS084974), the National Institute of Environmental Health Sciences (grant number R01 ES20395), the Department of Defense (ALSRP AL130125), the Mayo Clinic Foundation, the Mayo Clinic Center for Regenerative Medicine, the Mayo Clinic Center for Individualized Medicine, the ALS Association, the Alzheimer’s Association, the Robert Packard Center for ALS Research at Johns Hopkins, Target ALS, Canadian Institutes of Health Research, the Siragusa Foundation, the Robert and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Foundation, Project ALS, the Angel Fund, the Italian Ministry of Health (grant numbers EXOMEFALS 2009, NOVALS 2012 and RF-2009-1473856) and the European Commission.