Research Roundup updates as of March 2007:
NIH group finds no clear DNA clues to ALS
No significant genetic differences were found in a recent study of 276 people with sporadic (nonfamilial) ALS and 271 without the disease, says a report issued in February by a large group of U.S., British and Italian researchers.
Jennifer Schymick at the Neurogenetics Laboratory of the National Institutes of Health (NIH) in Bethesda, Md., and colleagues, who published their findings online Feb. 20 in Lancet Neurology, initially identified 34 DNA differences in their ALS-affected versus unaffected blood samples, all of which came from white, non-Hispanic U.S. residents with no family history of ALS. The study was funded by NIH, the Packard Center at Johns Hopkins University in Baltimore, and private organizations.
Among the identified differences were several in genes associated with the cytoskeleton, which is the scaffolding of cells, and genes that influence transport of compounds inside nerve fibers.
The investigators feared, however, that they might have identified “false positives,” meaning differences that appeared to be significant between the two groups actually weren’t. They therefore applied an extremely conservative mathematical procedure to their data analysis, after which none of the differences reached significance.
The MDA-supported Translational Genomics Research Institute (TGen) in Phoenix announced in November at an international ALS meeting in Yokohama, Japan, that it had identified significant genetic differences in the DNA of ALS-affected compared to unaffected study participants. (See “Genome-Wide Search Hits Pay Dirt,” January 2007.) The TGEN group expects to publish a paper in the near future.
That study, which compared the genomes (all genes) of 1,200 people with and 2,000 people without sporadic ALS, identified some 50 genetic differences in the two groups. Several are related to so-called adhesion proteins, which form molecular glue that holds cells in place.
“I think the two studies can’t be directly compared at this point,” said Sharon Hesterlee, MDA Vice President of Translational Research. “The TGen study, which has not yet been published, used somewhat different statistical methods and larger sample sizes. Ultimately, both studies will probably need to be confirmed independently before hard and fast conclusions can be drawn.”
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Do neurons have a unique stress response?
Motor neurons, the nerve cells that die in ALS, as well as other neurons, seem to have a particularly high threshold for activating a stress response that non-neuronal cells activate more easily, according to findings from the laboratory of MDA grantee Heather Durham at Montreal Neurological Institute at McGill University. That problem, if it could be remedied, might become a therapeutic avenue in ALS, the researchers say.
Building on work in the Durham lab and by Ian Brown at the University of Toronto at Scarborough, graduate student David Taylor and colleagues set out to decipher why the usual pathways for turning on protective stress responses are difficult to activate in motor neurons, whether or not they’re affected by ALS.
They found that neuronal cells don’t start production of protective compounds called heat shock proteins in response to the usual signals that activate these proteins in other cells.
The team, which published its findings in the January issue of Molecular and Cellular Neuroscience, identified a new pathway for turning on heat shock protein production in neurons, one that didn’t trigger this response in non-neuronal cells.
“These are clues pointing to alternative mechanisms of activating stress responses in neurons compared to other cells, and we’re continuing to try to identify these pathways,” Durham said.
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Canadian group makes nerve cells from skin
Francois Berthod at Laval University in Quebec City and colleagues say they’ve isolated cells that can become mature human neurons (nerve cells) from human skin cells, with implications for both research and treatment.
The investigators, who published their findings in the February issue of the Journal of Cellular Physiology, say they obtained skin cells from patients who had undergone breast reduction surgeries, grew them in plastic lab dishes in an environment that favors neuron development, and monitored them for seven weeks.
During that time, the cells went through the normal nerve cell developmental stages, producing proteins characteristic of each stage. They also began to form connections with each other, as nerve cells normally do.
In the near term, Berthod notes, the ability to produce human neurons from human skin cells could have a positive impact on research, because the inability of mature human neurons to divide makes these cells a scarce resource and forces most investigators to use animal nerve cells.
In the long term, Berthod says, it’s possible that replacement neurons could be produced from a patient’s own skin, thus eliminating the problem of rejection by the immune system.
“We are now trying to push the differentiation [maturation] of these neurons into a motor neuron fate,” says Berthod, who has MDA support for ALS research. (Motor neurons are the cells affected in ALS.) “That would be of great interest for the study of motor neuron diseases.”
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Avanir meets with FDA on Zenvia
Avanir Pharmaceuticals (www.avanir.com) of Aliso Viejo, Calif., announced on Feb. 28 that it has met with the U.S. Food and Drug Administration to respond to the agency’s concerns about Zenvia (formerly called Neurodex), the company’s product for “involuntary emotional expression disorder” (IEED, also known as pseudobulbar affect).
Zenvia is a combination of quinidine and dextromethorphan and was developed to help patients regain control of unwanted episodes of laughing or crying that can occur in some neurological disorders, including ALS. In October, the FDA raised concerns about the safety of Zenvia and declined to approve it.
In its press release, Avanir said it will conduct another clinical trial with a new formulation of Zenvia that reduces the amount of quinidine per dose from 30 milligrams to 10 milligrams. The company says it believes the drug will still be effective.
Check MDA’s Web site at www.als-mda.organd Avanir’s Web site for details as they become available.
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