ALS Research Roundup April 2008

by Margaret Wahl on Tue, 2008-04-01 17:00
Article Highlights:

Research Roundup updates as of March 2008

FDA confirms rat study results are reason for arimoclomol trial hold

According to a Feb. 11 press release from CytRx, developer of arimoclomol, the company has received written correspondence from the U.S. Food and Drug Administration (FDA) clarifying the agency’s decision to place a hold on the phase 2b trial of arimoclomol in ALS. (See “Arimoclomol trial,” MDA/ALS Newsmagazine, March 2008.)

The FDA has confirmed CytRx’s understanding that the agency’s decision pertained to a previously completed toxicity study in rats and was not related to data from any human arimoclomol studies.

Steven Kriegsman, CytRx’s president and CEO, is quoted as saying the company will “take the necessary steps to resolve this matter as expeditiously as possible” and that it plans to “work with the FDA to address their questions and allow us to move forward with our phase 2b trial.”

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What’s going on with TDP43?

Two new research papers, both published in February, show that mutations (flaws) in the gene for the TDP43 protein can result in familial and sporadic (nonfamilial) ALS.

Nigel Cairns at Washington University School of Medicine in St. Louis, and colleagues, announced online Feb. 20 in Annals of Neurology that a mutation in the gene for TDP43 is the cause of ALS in a family of European descent.

And a week later, Christopher Shaw at King’s College London, and colleagues, published findings online in Science Express showing that a TDP43 mutation caused ALS in a family of British descent and in a few people with nonfamilial ALS. (Out of 2,500 unaffected people who also were screened, only one had a TDP43 mutation.)

These findings come shortly after the announcement last spring that abnormal cellular clusters containing TDP43 are present in sporadic ALS and in the type of familial ALS that’s not related to the SOD1 gene, but are not present in SOD1-related ALS; and a subsequent finding that a deficiency of the protein progranulin leads to fragmentation and mislocation of the TDP43 protein in cells.

These results could mean TDP43 is a factor in the ALS disease process and that its apparent involvement only in non-SOD1 ALS signifies a difference between SOD1-related ALS and the other more common forms of the disease.

Scientists now should be able to breed mice with TDP43 mutations and further explore TDP43’s actions.

“It will be very interesting if academics can develop a TDP43 animal model that mimics ALS in a robust fashion,” wrote John McCarty, treatment investigator at the MDA-supported ALS Therapy Development Institute in Cambridge, Mass., on the Institute’s online forum ( March 4. McCarty cautioned that the presence of TDP43-containing clusters in ALS-affected cells doesn’t necessarily mean the protein plays a disease-causing role.

However, he noted, mice with TDP43 mutations “would be a very welcome new tool for us and other researchers.”

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Nerve-muscle signals are a two-way street

Nerve Cells Illustration

Chemical signals from nerve cells are known to influence muscle cells. Lin Mei’s team has found that signals from muscle cells also influence nerve cells.

Researchers in the laboratory of MDA-supported Lin Mei at the Medical College of Georgia in Augusta have found that muscle fibers do more than passively receive signals from nerve fibers that tell them to contract or relax.

Instead, say Mei and colleagues, who published their findings online in Nature Neuroscience Feb. 17, “backwards” (retrograde) signals coming from muscle fibers to nerve fibers profoundly influence nerve-fiber location and function. The finding could have implications for ALS, in which nerve cells that interact with muscle fibers degenerate.

When the investigators bred mice lacking a protein called beta-catenin in their muscles, they saw that branches of the phrenic nerves, which go to the respiratory diaphragm, were mislocated in the diaphragm muscle and that signal transmission was reduced.

However, when beta-catenin was depleted only in nerve cells in the mice, they didn’t have this type of neurological problem.

“These observations demonstrate that muscle beta-catenin is a key ingredient for neuromuscular junction formation,” Mei said, referring to places where nerve and muscle fibers meet. The findings also showed that beta-catenin may control other proteins necessary to nerve-cell health, she added.

“Muscles are known to produce elusive nutritional factors for nerve-cell survival and development,” Mei said. “And these findings could provide leads to their identification.”

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VEGF-B may save nerve cells without collateral damage

A protein called vascular endothelial factor B (VEGF-B) appears to protect nerve cells without causing unwanted proliferation of blood vessels, as its chemical relative VEGF can do, says a new report in the Journal of Clinical Investigation.

Xuri Li at the National Institutes of Health in Bethesda, Md., and colleagues, who published their results online Feb. 7, describe how treatment with VEGF-B injections rescued nerve cells in mice with injuries to the retina and optic nerve, without undesirable effects. They conclude that VEGF-B might provide a new option for treating different types of neurodegenerative disease.

MDA is funding Peter Carmeliet at the Flanders Interuniversity Institute for Biotechnology in Ghent, Belgium, to study VEGF and VEGF-B in rodents with ALS.

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Review of evidence supports link between toxic exposures and illness in Gulf War vets

A review of multiple studies of veterans of the 1990-1991 Persian Gulf War who developed ALS and other illnesses strongly supports a link between illness and exposure to chemicals known as acetylcholinesterase inhibitors (AChEis). (This topic was explored in “ALS and Vets: Searching for Connections” in the March 2008 issue.)

In this new review, published March 18 in Proceedings of the National Academy of Sciences, Beatrice Golomb at the University of California-San Diego describes 21 studies of Gulf War veterans that link this type of chemical exposure to later development of a variety of health problems.

The AChEis studied included pyridostigmine bromide, a medication given to some 250,000 Gulf War service personnel to counteract expected attacks with toxic nerve agents; carbamate and organophosphate pesticides, which were aggressively used in that conflict to control insects and to which 41,000 service members may have been overexposed; and sarin, a nervous-system toxin to which the Department of Defense estimates about 100,000 personnel were possibly exposed after demolition of a munitions depot.

The review also found that low activity levels of two enzymes involved in detoxification of AChEis (PON and BChE enzymes) also correlated with the presence of illness. Genetic variations are one cause of activity level variation in these enzymes.

The author notes that emerging evidence links ALS incidence to PON gene variants and perhaps their interaction with AChEi pesticides. She says this evidence supports a connection between organophosphate pesticide exposures during the Gulf War and the observed elevated rate of ALS development in Gulf War veterans.

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Margaret Wahl
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