ALS Research Roundup Nov. - Dec. 2008

by ALSN Staff on Mon, 2008-12-01 09:16
Article Highlights:

Research Roundup updates as of October 2008:

Stem cells entered nervous system but didn’t slow ALS

Although six men with ALS who received intravenous infusions (“transplantations”) of donated bone marrow stem cells failed to derive any apparent benefit from the procedure, the study showed that such cells can enter the central nervous system from the bloodstream, an important finding.

The ability of stem cells to enter the nervous system by penetrating the barriers surrounding the brain and spinal cord supports their potential use as carriers of therapeutic substances, such as neurotrophic factors (see “Supercharged stem cells.”)

MDA grantee Stanley Appel at Methodist Neurological Institute in Houston coordinated the study team, which published its results in the Oct. 14 issue of Neurology. (Appel, director of the MDA/ALS Center at Methodist Neurological Institute, is a member of the MDA Board of Directors and chairman of MDA’s Medical Advisory Committee.)

Stan Appel
MDA grantee Stan Appel coordinated a study team that found that donated bone marrow stem cells can enter the nervous system in people with ALS, and that immune-system T-cells provide an unexpected benefit in ALS mice.

Appel said the results, while important, should serve as a warning to patients not to believe the “hype” surrounding currently advertised stem cell treatments for ALS.

In the recently published study, six men with sporadic (nonhereditary) ALS, ranging in age from 35 to 59, underwent radiation treatment to partially destroy their own bone marrow, followed by medications to suppress their immune systems and help them accept bone marrow stem cells donated by siblings.

All study participants accepted the donated cells, with four of the six eventually showing 100 percent donated cells in their bloodstreams.

Three patients had rapid progression of their ALS following transplantation, with no evidence of clinical benefit.

A fourth experienced slow loss of function and required invasive (tracheostomy-delivered) respiratory support about three years later.

Another experienced slow disease progression for the first 14 months after transplantation and then rapid disease progression.

Only one patient’s ALS progressed at an overall rate that was slower than average for this disease, living for 7.5 years after symptom onset. The investigators say his age (35 at study enrollment), rather than the bone marrow transplant, was the likely cause of his slow disease progression.

In three study participants, the brain and spinal cord were examined after death.

Two patients who had shown 100 percent donor cells in their blood showed 16 percent to 38 percent donor DNA at sites of ALS injury in the spinal cord. Both also showed donor DNA in the parts of the brain that their symptoms indicated were the most affected by the disease.

In the third patient, whose blood had carried only a small percentage of donor cells, there was no donor DNA in the spinal cord or brain.

The donated cells showed a marked preference for sites of injury, areas to which molecular “damage signals” may have attracted them.

“This first long-term study of bone marrow stem cell transplantation in ALS in humans is important,” Appel said, “in that it showed us that donated cells can get into the brain and spinal cord and home to the sites of injury specifically.

“Our study showed no real clinical benefit for ALS patients, which should send a warning not to believe the exaggerated claims for stem cell transplantation in ALS at the present time.

“However, although stem cells by themselves didn’t provide any benefit to the patients, further studies in which stem cells serve as delivery vehicles for therapeutic genes or proteins may prove of value, especially since donor cells appear to enter areas of the nervous system at sites of ALS injury.

“Risky injections of donor cells containing therapeutic compounds directly into an ALS patient’s spinal cord would probably not be required. Instead, delivering potentially therapeutic compounds via bone marrow stem cells could probably be accomplished with infusions into the bloodstream.”

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Supercharged stem cells save nerve cells, lengthen life span in ALS rats

Stem cells
Stem cells (Photo: Emanuela Gussoni, Children’s Hospital, Boston)

Scientists at the University of Wisconsin-Madison and institutions in the United Kingdom and Switzerland have shown that stem cells derived from human bone marrow and engineered to produce a neuroprotective substance can significantly slow symptom progression in rats with a disease resembling human ALS.

Masatoshi Suzuki and Clive Svendsen, both at the University of Wisconsin’s Waisman Center, and colleagues, published their findings online Sept. 16 in Molecular Therapy. They say the stem cells acted as miniaturized long-term “pumps” that delivered GDNF (glial-derived neurotrophic factor) to the rats after being injected into their muscles. The neuroprotective compound apparently traveled to nerve cells from the muscle tissue. (A recent human study showed such cells can reach the nervous system via the bloodstream. See “Stem cells.”)

Rats with mutated SOD1 genes and a disease resembling human ALS that were treated with the supercharged stem cells lived as much as 28 days longer than their untreated counterparts. Even in rats with a very severe, rapidly progressive disease, caused by high numbers of mutated SOD1 genes, the average survival time was prolonged by 18 days.

The stem cells the researchers used, known as “mesenchymal” stem cells, normally give rise to bone, muscle, cartilage, tendons or fat cells. The investigators note that these stem cells, even without being supercharged to produce GDNF, secrete other proteins that may be neuroprotective, reduce inflammation and enhance blood-vessel formation.

In fact, the stem cells preserved significant numbers of motor neurons, the nerve cells that control muscle activity that are lost in ALS, even when they didn’t produce GDNF. However, the benefit was greater when the cells were equipped with GDNF genes.

The researchers note that muscle is an accessible tissue compared to the nervous system and that delivering GDNF or other protective genes via stem cells has advantages over other gene therapy approaches.

For instance, they say, delivering therapeutic genes directly to the recipient’s existing cells, which are already undergoing ALS-related degeneration, might not be as beneficial as delivering these genes via new cells that are healthy and bring additional advantages to the targeted areas.

“This was a combined therapy approach,” Svendsen said. “Both the stem cells, and the GDNF they released, seemed to work together to provide these effects.”

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T cells provide protection in ALS mice

T cells, the foot soldiers of the immune system, are involved in protecting motor neurons (nerve cells that activate muscle) in ALS, says a group of scientists led by MDA grantee Stanley Appel at Methodist Neurological Institute (NI) in Houston.

Methodist Hospital
Methodist Hospital in Houston, home to the MDA/ALS Center in the Methodist Neurological Institute (Photo: The Methodist Hospital System)

Lead authors David R. Beers and Jenny S. Henkel, working with Appel at NI, published their findings online Sept. 22 in Proceedings of the National Academy of Sciences.

First, the researchers developed mice with a disease resembling human ALS but without functional T cells and another group of mice with the same ALS-like disease but with functional T cells. They found that the mice without the T cells had an accelerated disease course and died earlier than the mice with T cells.

When the ALS mice lacking functional T cells were given an infusion of bone marrow stem cells, T cells appeared in their spinal cords, apparently from the infused stem cells. Their disease course slowed, and their survival was extended compared to the ALS mice without T cells. (These experiments were designed to test whether ALS mice did better with or without T cells and didn’t test whether extra T cells or bone marrow stem cells would be beneficial.)

The findings came as somewhat of a surprise, Appel says, since his team had expected that T cells would be toxic and not protective in the nervous system in ALS. Previous studies, some of which were conducted in his laboratory, had shown that other immune system cells, called microglia, can cause dangerous inflammation in the central nervous system, the site of injury in this disease.

However, he notes, “It turns out that activated T cells can be a good thing in ALS. Instead of animals living longer with no T cells, they died in a shorter period of time.”

The investigators zeroed in on “CD4-positive” T cells as the T-cell type that’s likely conferring the benefit. “At least in this animal model, CD4 T-cells are critical,” Appel said. “T cells in general modulate the complex activities of the immune system, and our study demonstrates that they can be neuroprotective.” Appel added that T-cell therapy could be of value in human ALS, although further studies are needed.

“It’s been known for some time that T cells are present at sites of injury in ALS patients as well as in mouse models of ALS,” said investigator David Beers. “But until now, the role of these cells was unknown. This study demonstrates that T cells, through their interaction with other cells in the immune system, are protecting the cells in the spinal cord that cause muscle movement. It’s now critically important to understand how T cells provide this neuroprotection.”

Investigator Jenny Henkel noted, “These [CD4 T] cells may eventually provide a readily accessible target for therapeutic intervention, not only for ALS but other neurodegenerative diseases.

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FDA finds no connection between statins and increased ALS risk

Taking cholesterol-lowering medications known as statins does not appear to increase the risk of developing ALS, said the U.S. Food and Drug Administration in a statement released Sept. 29. The agency recommended no change in the prescribing guidelines for these drugs.

In June 2007, the World Health Organization reported in the journal Drug Safety that there might be a connection between statin use and an ALS-like syndrome. (See “ALS-statin interactions probed,” ALS Newsmagazine, September 2007.)

After its own adverse event reporting system signaled further investigation of the subject was warranted, the FDA undertook an extensive review of a possible connection between ALS development and statins such as atorvastatin (Lipitor), lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor) and others.

Eric Colman, a physician in the Division of Metabolism and Endocrinology Products at the FDA’s Center for Drug Evaluation and Research, coordinated a group of FDA-based specialists in cardiovascular disease, neurology, epidemiology and statistics that analyzed data from 41 clinical trials of statins.

Pill bottle
The Food and Drug Administration found that cholesterol-lowering drugs (statins) didn’t appear to increase the risk of developing ALS, but the case isn’t completely closed.

The investigators, who published their findings online Sept. 29 in Pharmacoepidemiology and Drug Safety, only included clinical trials that lasted at least six months and in which statins were compared to a placebo (inert, look-alike substance).

Among participants in the statin trials, they found nine people who were on a statin who developed ALS and 10 who were taking a placebo and developed ALS. “Although we observed a ... signal for ALS with statins in FDA’s AERS [adverse event reporting system], retrospective analyses of statin clinical trials did not reveal an increased incidence of ALS in subjects treated with a statin compared with placebo,” the researchers concluded.

They also noted that the antiinflammatory properties of statins and the relatively stable incidence of ALS in the United States over the past two decades, despite a 30-fold increase in statin use, argue against the possibility that statins cause ALS.

However, they say, because these drugs are widely prescribed and ALS has such dire consequences, “any degree of uncertainty justifies further investigation.” They’re expecting results from a study now under way through MDA grantee Lorene Nelson at Stanford (Calif.) University to shed further light on this subject. Nelson, an epidemiologist, has MDA funding to conduct a “case-control” study of ALS and cholesterol-lowering medications, including statins, in which she’s comparing the medication histories of people with and without ALS.

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ALS Registry Act passed

On Sept. 23, the U.S. Senate passed the ALS Registry Act, authorizing creation of a national registry to gather and store data on ALS. (The U.S. House of Representatives passed similar legislation in 2007.) The federal Centers for Disease Control (CDC) will be responsible for creating the registry and coordinating research.

“Registries are very helpful in identifying trends that should be followed up in research studies,” said Valerie Cwik, MDA medical director and senior vice president of research. “We’re hopeful that a national ALS database will result in enhanced efforts to define treatments.” MDA is currently funding the ALS Connection registry at

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ALS disability benefits for vets confirmed

The Veterans Administration (VA) confirmed in September that, “the development of ALS at any time after discharge or release from active military, naval, or air service is sufficient to establish service connection for that disease.”

Prior to this time, only veterans with ALS who had served in the Gulf War (August 1990-February 1991) were accorded “service-connected disability” status by the VA. It’s the agency’s highest disability rating, and it makes the greatest degree of no- or low-cost VA medical care available.

“For seven years, the ALS advocacy community has pushed to get all ALS-affected service people included in that package of care,” said MDA Vice President of Advocacy Annie Kennedy. “This is wonderful news for the ALS community.”

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To the editor

I was diagnosed with ALS in 2005. I was reading of the correlation of ALS with Gulf War service, possibly due to nerve gas exposure.

During my years in the Navy, 1944 to 1946 active duty, I underwent training at the Amphibious Training Base in Little Creek, Va., in 1944. As part of my unit’s training, we were deliberately exposed to the gas Luicite. Our superior officers told us to stand in a circle and there was a small vial of Luicite gas exploded in the center of the group so we would recognize the smell.

Unfortunately, a big gust of wind blew the liquid portion of the Luicite gas on approximately 10 of us standing together on one side of the circle. We were hospitalized for several days, some for more than a week or 10 days. Those who were hospitalized for longer than three days had to be reassigned to new ships.

It would be interesting to locate those men who were hospitalized from my group and other groups as a result of similar deliberate gas exposure training exercises. I would like to know if this exposure increased our risk of ALS.

My exposure was approximately October 1944.

Elroy Schoppa
La Habra, Calif.

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