ALS Research Roundup Jan.-Feb. 2010

by ALSN Staff on Fri, 2010-01-01 10:48
Article Highlights:

Update on research, clinical trails and studies as of December 2009

The items in this article address research in ALS as of December 31, 2009, on these topics: Gulf War connection, smoking, serum lipids, arimoclomol study, microRNA 206 potential.

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Soil bacteria implicated in ALS-Gulf War connection

In 2001, a government-funded study showed that military personnel serving in the Gulf War in 1990-1991 were nearly twice as likely to have developed ALS as were military personnel who had not served in that war.

The study analyzed the records of nearly 700,000 U.S. soldiers deployed between Aug. 2, 1990, and July 31, 1991, to fight in the Persian Gulf War against Iraq. Of those, 40 eventually developed ALS, which is roughly twice the rate of ALS cases found in 1.8 million veterans who weren’t deployed to that region during the same period.

Since then, epidemiologists and biologists have speculated that some combination of genetic susceptibility and environmental factors, such as toxins, pollutants or viral infections, may have converged to cause the unusually high rate of ALS cases in the Gulf War group (even though the absolute numbers remained small).

In a study published online Nov. 10, 2009, in the journal Amyotrophic Lateral Sclerosis, Paul Cox of the Institute for EthnoMedicine in Jackson, Wyo., and colleagues, implicate desert dust containing microorganisms called “cyanobacteria” as a possible cause of the increase in cases.

The dry, crusty landscape of the region is rich in cyanobacterial crusts and mats, which help bind the desert sands, the study’s authors say. When these are disturbed by vehicles or other military activiies, they can produce significant dust, which contain known neurotoxins BMAA and DAB. “If dust containing cyanobacteria is inhaled,” they write, “significant exposure to BMAA and other cyanotoxins may occur. We suggest that inhalation of BMAA, DAB, and other aerosolized cyanotoxins may constitute a significant risk factor for the development of ALS and other neurodegenerative diseases.”

They also note that a major criticism of the initial reports of an increased incidence of ALS among Gulf War veterans was the lack of evidence for a “biologically plausible” environmental factor that could contribute to such an increase. The authors, which include former MDA research grantee Walter Bradley at the University of Miami, say cyanobacterial exposure is such a factor.

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Smoking is a risk factor for ALS

A new analysis says that smoking, already suspected of being a risk factor for ALS, definitely is one.

Carmel Armon, professor of neurology at Tufts University School of Medicine in Boston and chief of neurology at Baystate Medical Center in Springfield, Mass., analyzed the medical literature published on smoking and ALS between 2003 and April 2009.

He initially identified 28 studies, only two of which were considered reliable enough to be included in the final results, which were announced Nov. 17, 2009, in the journal Neurology.

The first paper Armon references was published in 2007 in Neurology. It reports on the occupation, education and smoking habits of 364 people with ALS and 392 without the disease in the Netherlands. Smoking was the only factor the researchers studied that, by itself, increased the chance of developing ALS. It raised the risk of the disease 1.6 times over average.

The second study, published in Annals of Neurology in 2009, looked at people who were part of the European Prospective Investigation into Cancer and Nutrition (EPIC) database. Out of 517,890 initially healthy subjects, 118 ultimately died of ALS.

Those who reported they were currently smoking at the time they entered the study had almost twice the risk of dying from ALS (1.89 times greater than average) compared to those who never smoked.

Those who classified themselves as “former smokers” at the time of study enrollment had 1.48 times the risk of dying from ALS compared with those who had never smoked.

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Italian study adds to uncertainty about serum lipids and ALS

In 2008, a French research group published a somewhat surprising study that suggested high levels of lipids (fats, such as cholesterol and triglycerides) in blood serum might be more common in people with ALS than in the general population but at the same time might actually improve survival time once the disease develops. (See “Does a high serum cholesterol level increase survival time in ALS?” in the May 2008 ALS Newsmagazine.)

Now, adding to the uncertainty are results of a study conducted in Italy and published Nov. 17, 2009, in Neurology. These investigators found no differences between serum lipid levels in 658 people with ALS and 658 without the disease. Nor did they find that high serum lipids were related to longer survival in those with ALS. However, they did find that respiratory impairment was correlated with lower blood lipid levels in the ALS group.

The researchers say one explanation for the observation is that, as respiratory muscles decline in strength, more energy expenditure is needed for breathing, which in turn may lower blood lipid levels.

They say their findings do not support the French researchers’ conclusion that people with ALS have a tendency to have high serum lipids or that high serum lipid levels in this population are related to longer survival.

The jury is still out on whether or not there is any relationship between serum lipid levels and ALS, and MDA researchers are studying this question.

Lorene Nelson at Stanford University in California has received MDA funding to study whether cholesterol-lowering medication increases the risk of developing ALS or influences its rate of progression after it develops.

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FDA says ALS arimoclomol study can reopen

A multicenter clinical trial of arimoclomol, an experimental compound being developed by CytRx Corp. (www.cytrx.com) of Los Angeles, will resume, with a revised protocol, the company announced Dec. 2, 2009. The trial is funded by CytRx.

Arimoclomol is designed to activate molecules called “chaperones,” which help regulate cellular repair. According to CytRx, arimoclomol can detect proteins that are misfolded and potentially toxic and refold them into their correct, nontoxic shapes.

The U.S. Food and Drug Administration (FDA) placed a hold on this phase 2b trial of arimoclomol in January 2008, saying it wanted to see more toxicity data from previously completed animal studies.

The new trial, which has not yet officially opened, will test arimoclomol in groups of 20 to 30 people with ALS at a time, starting with a dosage level of 100 milligrams three times a day and increasing the dosage level by 75 milligrams per dose up to a maximum of 400 milligrams three times daily. An independent safety monitoring board will review results before each dosage increase.

Each group will receive arimoclomol for three months. Fifteen people will receive a combination of arimoclomol at various dose levels plus riluzole (Rilutek), an established treatment for ALS, at a fixed dose of 50 milligrams twice daily; and another five to 15 people will receive a placebo plus 50 milligrams of riluzole twice a day.

The two principal investigators are Merit Cudkowicz, director of the MDA/ALS Center at Massachusetts General Hospital in Boston; and Jeremy Shefner, director of the MDA/ALS Center at the State University of New York Upstate Medical University in Syracuse.

In addition to looking at safety, the investigators will evaluate participants’ scores on the revised ALS Functional Rating Scale, as well as their vital capacity (a respiratory measurement) results. However, the trial is designed only to note extreme responses in these two categories.

For information about this trial, see the clinical trials section of MDA’s Web site, or contact Elizabeth Simpson at (877) 458-0631 or esimpson1@partners.org.

For information about a separate trial of arimoclomol in the SOD1 form of familial ALS, see the clinical trials section of MDA’s Web site. Or contact Darlene Pulley at dpulley@partners.org for the Boston site; or write to sod1@emory.edu for the Atlanta site.

Normally, nerve cells signal muscle fibers through a chemical called acetylcholine. In ALS, as nerve cells are damaged, these connections are disrupted. New findings suggest microRNA 206 participates in restoring these connections after inquiry.

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Scientists say microRNA 206 could have therapeutic potential

A molecule called microRNA 206, produced by muscle fibers after an injury to nerve cells, helps rebuild crucial nerve-muscle communications, say scientists at the University of Texas Southwestern Medical Center in Dallas and Harvard University. Loss of such connections is an aspect of ALS in mice and humans.

After finding that mice with an ALS-like disease fared worse without microRNA 206 than with it, researchers said raising levels of this compound or amplifying its effects in some other way could become a new therapeutic avenue.

Eric Olson at the University of Texas Southwestern Medical Center in Dallas, with colleagues there and at Harvard University, reported the new findings in the Dec. 11, 2009, issue of the journal Science.

When the scientists genetically engineered mice to develop an ALS-like disease and also to lack microRNA 206, they found the mice had faster disease progression and died earlier than mice with the same disease that had normal microRNA 206. However, mice with and without microRNA 206 developed their first disease symptoms at about the same time.

That and other experimental results led the investigators to the conclusion that microRNA 206, which comes from muscle fibers, acts in response to injury to nerve tissue and becomes important only after such injury occurs. The compound appears to help compensate for the ALS-related nerve injury, albeit incompletely.

While there are no immediate implications for people with ALS, investigators Eric Olson and Andrew Williams, both at UT Southwestern, have filed patent applications related to these results, indicating they may believe it has potential for drug development.

In addition to his academic position, Olson is a co-founder of and chief scientific adviser to miRagen Therapeutics (www.miragentherapeutics.com), a Boulder, Colo., biotechnology company that develops microRNA-based therapeutics for cardiovascular and muscle diseases.

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ALSN Staff
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