ALS Research Roundup September 2008

by Margaret Wahl on Mon, 2008-09-01 15:16
Photo of unidentified soldier from istockphoto.com / 2008
Article Highlights:

Updates on research, clinical trials and studies as of August 2008

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Military personnel who spent significant time in Saudi Arabia near the Kuwaiti border in 1990-1991 had the highest estimated risk of developing ALS.

Study suggests Gulf War-associated increase in ALS is time-limited and correlated with location

U.S. veterans of the first Gulf War don’t have a permanently increased chance of developing ALS, according to a study supported by the Department of Veterans Affairs and the Department of Defense and published online June 6 in Neuroepidemiology.

“Basically, the outbreak has run its course,” said Ronnie Horner, a professor at the Institute for the Study of Health at the University of Cincinnati and an author on the study. “The excess risk appears to have dissipated.”

Horner, with colleagues at other universities and at Veterans Affairs Medical Centers, compared the incidence of new ALS cases that occurred between 1991 and 2001 in two groups: 700,000 military personnel deployed to the Persian Gulf region in 1990-1991, in whom 48 cases occurred; and 1.8 million people who were in the military during that period but weren’t sent to the Gulf, in whom 76 cases occurred.

They found those who didn’t go to the Persian Gulf region in 1990-1991 had a low incidence of ALS compared to the average risk for men in western Washington state during this entire period; but that those who served in the Gulf region showed a consistently higher incidence of ALS compared to average Washington state men and to the non-Gulf-deployed military population during some of those years.

The incidence of new ALS cases steadily increased among Gulf-deployed personnel between 1994 and 1996, about four to six years after deployment, peaking in 1996, after which it declined. By 2001, their risk was the same as for the non-deployed military personnel and below the risk for the male Washington state population in general.

The data suggest there were specific exposures or other events associated with the first Gulf War that, perhaps in combination with genetic susceptibility factors, led to a temporary rise in ALS cases.

“We have to keep a very open and creative mind here,” Horner said. “It may not be any single exposure or single factor. It may be multiple exposures to multiple agents.”

In another study, published online in Neurotoxicology June 20, Marie Lynn Miranda at Duke University, and colleagues, analyzed troop movements in the Gulf region during the war to see if they could determine whether being in a particular location influenced a soldier’s chance of incurring an elevated ALS risk.

They determined that military personnel who spent significant time in Saudi Arabia near the Kuwaiti border had the highest chance of an elevated ALS risk. A soldier who spent 126 days (about four months) in this area would have twice the average risk of developing ALS, the investigators concluded. (Even an elevated risk still yields small numbers of ALS cases. On average, about two people out of every 100,000 will develop ALS in a given year. Twice that would mean four people.)

In March 1991, U.S. Army units destroyed munitions depots in Khamisiyah, located in southeastern Iraq near the Kuwaiti and Saudi Arabian borders. Later, when these bunkers and warehouses were found to contain chemical weapons, the Department of Defense determined some 100,000 soldiers may have been exposed to low levels of nervous-system toxins.

The study team, which included Ronnie Horner, who was also part of the Neuroepidemiology study analyzing the duration of elevated ALS risk, emphasizes that no particular toxic exposures have yet been linked to the development of ALS in Gulf War veterans and that this latest study only suggests a geographic correlation.

However, they say, exposure to the munitions depots in Khamisiyah and to smoke from oil-well fires are candidate risk factors that are consistent with the location data. They note that further studies should attempt to correlate troop locations with exposures and other candidate risk factors.

“The next step is to see whether there is a time dimension to the risk associated with specific geographic locations; that is, is a specific geographic location at a specific time associated with an elevated risk of ALS?” Horner said. “For example, we need to know whether the troops who developed ALS were in the same location at the same time that the oil-well fire smoke plumes or the low-level nerve- agent plume were present.”

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ALS TDI finds lithium ineffective, apocynin ambiguous in ALS mice

Scientist in Lab
ALS TDI scientists found no benefit from lithium in ALS mice. However, investigators caution that a negative result in the mouse doesn’t necessarily predict one in humans.

The ALS Therapy Development Institute (ALS TDI), an MDA-supported laboratory in Cambridge, Mass., announced results of mouse studies of lithium and apocynin July 11.

The ALS TDI’s independent study of lithium indicated no observable survival or functional benefit in the ALS mouse.

John McCarty, treatment investigator at the ALS TDI, said he was confident of the mouse results but that "the value of using the mouse model tool is not necessarily to conclude a therapeutic can't work in humans; such a determination can really only be made with proper clinical trials."

The ALS TDI team also conducted two ALS mouse studies of apocynin, a molecule that interferes with damaging byproducts of cellular metabolism.

The ALS TDI scientists compared disease progression in ALS mice that received apocynin starting at day 50 (late start) and then at day 30 (early start) to progression in control (untreated) ALS mice.

The scientists didn’t see indications of strong efficacy in the mouse model, but they did see a weak trend toward extension of survival in female mice that started on apocynin at age 30 days. The trend didn’t reach statistical significance, but the Institute plans to repeat the early-start study.

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VA broadens ALS care coverage, while studies of veterans continue

On July 14, James Peake, Secretary of Veterans’ Affairs at the U.S. Department of Veterans Affairs, announced the Department will broaden its coverage of ALS as a service-connected disability for all veterans, not just those who served in the 1990-1991 Gulf War. Peake informed lawmakers of his decision on a conference call.

US Soldiers
The U.S. Veterans’ Affairs Department recently announced that ALS will be covered as a service-connected disability for all veterans, not just those who served in the Gulf War.

A study of all veterans with ALS is now under way, utilizing data from the National Registry of Veterans with ALS, established in 2003 by the U.S. Department of Veterans Affairs. (The Registry closed in September 2007.)

The new study, Genes and Environmental Exposures in Veterans with ALS (GENEVA), will compare records and DNA samples from veterans with ALS to data from veterans without the disease to evaluate the contributions of genetic susceptibilities and environmental exposures to the risk of developing ALS.

Silke Schmidt of Duke University Medical Center in Durham, N.C., with colleagues from Duke, the National Institutes of Health, and other institutions, described the study’s methodology online April 18 in Neuroepidemiology.

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MDA-supported lithium study now open at 10 sites

An MDA-funded, 100-person study of lithium carbonate in ALS is now open at 10 U.S. centers. The new study will be open label, meaning there will be no placebo (inert substance) group. Trial sites are in San Francisco, Los Angeles, St. Louis, Philadelphia, Houston, Salt Lake City, Scottsdale (Ariz.), Orange (Calif.), Kansas City (Kan.) and Portland (Ore.). 

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Umbilical-cord blood cells may have therapeutic potential in ALS

An intravenous infusion of human umbilical-cord blood cells significantly extended the life span of SOD1 mice, which have an ALS-like disease, as well as prolonged their motor function and decreased biochemical evidence of inflammation.

Svitlana Garbuzova-Davis, at the University of South Florida in Tampa, with colleagues there and at Saneron CCEL Therapeutics in Tampa, tested three different dosage levels of human cord-blood cells in the mice and then compared these mice to SOD1 mice receiving no treatment or treatment with cyclosporine, an immunosuppressant drug.

Mice receiving the moderate dose of cord-blood cells showed a 15 percent decrease in disease progression in terms of measured motor function at certain time points, and they lived more than 20 percent longer than either untreated or cyclosporine-treated mice.

Mice treated with this most effective dose of cells also showed significantly less evidence of inflammation in the central nervous system, as measured by biochemical and cellular tests, than untreated or cyclosporine-treated mice.

Results from mice receiving the other two doses of human umbilical-cord blood cells weren’t much different from those of the untreated or cyclosporine-treated mice on most of the tests.

The investigators, who published their findings in the June issue of PLoS One, say they believe their results demonstrate that treatment of ALS with human umbilical-cord blood cells at the right dose might have a protective effect on degenerating neurons (nerve cells) by dampening harmful inflammatory and immune-system responses in ALS.

“Developing an effective treatment for ALS is complicated by the diffuse nature of motor neuron death,” said Garbuzova-Davis, referring to the large areas of muscle-controlling nerve cells affected in this disease. “However, cell therapy may offer a promising new treatment.”

Garbuzova-Davis has MDA funding to study barriers between the bloodstream and nervous system in ALS.

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FDA approves diaphragm pacing system to treat people with spinal cord injuries

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The NeuRX diaphragm pacing system stimulates the diaphragm to contract and descend, allowing air to flow into the lungs. Illustration courtesy of Synapse Biomedical

The U.S. Food and Drug Administration (FDA) has approved the NeuRX Diaphragm Pacing System for patients with spinal cord injuries who lack voluntary control of the respiratory diaphragm, opening the door to greater future availability of this device for people with ALS.

The NeuRX system provides paced electrical stimulation to the diaphragm muscle and the nerve fibers that run through it. When stimulated by surgically implanted electrodes, the diaphragm contracts, mimicking natural breathing by allowing air to flow into the lungs. The system is designed to partially substitute for or replace a positive-pressure ventilation device, which forces air into the lungs through a mouthpiece or other interface.

NeuRx’s manufacturer, Cleveland-based Synapse Biomedical (see www.synapsebiomedical.com), announced the FDA’s approval June 17, noting the agency’s decision was based on studies of the system in 50 patients with spinal cord injuries since 2000.

A study of the pacing system in ALS is being conducted in Cleveland, Baltimore and Stanford, Calif. 

If you’re in the study, the device itself is free, but the associated surgery and care are not. These costs are about $5,000, which in some cases may be covered by private insurance. These costs are also eligible for coverage under Medicare Part B. See the Synapse Web site’s ALS Reimbursement section, or contact the company at (440) 774-4043, for details.

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MDA/ALS Center directors produce collection of articles about ALS

Greg Carter and Michael Weiss, co-directors of the MDA/ALS Center at the University of Washington Medical Center in Seattle, are the editors of the August issue of Physical Medicine and Rehabilitation, which is devoted largely to ALS. The articles, many of which are written by MDA/ALS Center directors, cover a wide range of topics, such as genetics, quality of life and pulmonary support. The issue is available through the publisher’s Web site at www.us.elsevierhealth.com for $99 or by calling (800) 654-2452.

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Margaret Wahl
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