ALS Research Roundup April 2009

by Margaret Wahl on Wed, 2009-04-01 09:16

Several advances made in ALS genetics

Article Highlights:

Research Roundup updates as of March 2009:

Items in this article report on research findings as of April 1, 2009, including: genetic causes of ALS, familial ALS, arimoclomol, SOD1 ALS, modafinil, Iplex, ceftriaxone, lithium, stem cell model of ALS.


Not long ago, doctors were quick to answer the question “is ALS genetic?” with “only about 10 percent of the time.”

That’s still true, if you’re talking about a predictably inherited, disease-causing gene that leads to more than one case in a family. Those cases, known as “familial” ALS, are still thought to make up only about 10 percent of the ALS population (although there are many more genes within that 10 percent than previously thought).

But the last few years have seen an explosion in knowledge about the influence of genetics on the likelihood of developing ALS and on its rate of progression and severity. As with many diseases previously considered “not genetic,” ALS often occurs when genetic susceptibilities coincide with nongenetic factors. In this disease, unfortunately, those largely remain undefined, although toxic exposures (such as in the first Gulf War), viruses and head injuries are among the suspects.

Although some of the identified genes implicated in ALS only cause the disease in a tiny fraction of patients or only make a small contribution to disease susceptibility, understanding what these genes normally do and what goes wrong when they don’t do it should ultimately help investigators unravel the larger ALS tapestry.

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Mutations in FUS gene cause familial ALS

Two independent research teams, one based in the United States and Canada and the other in the United Kingdom and Australia, have identified mutations in a gene called FUS on chromosome 16 as a cause of familial (inherited) ALS. Both groups announced their findings in the Feb. 27, 2009, issue of the journal Science.

group family photo
Some genetic mutations are known to cause ALS by themselves, while others appear to increase susceptibility to the disease.

Mutations in the newly implicated FUS gene are thought to account for some 3 percent to 5 percent of familial ALS cases, or 0.3 percent to 0.5 percent of all ALS cases.

However, the identification of a new gene is likely to shed light on additional mechanisms underlying ALS, lead to the creation of new rodent models for the disease and may ultimately lead to identification of new therapeutic avenues.

The U.S. and Canadian team was coordinated by Thomas Kwiatkowski at Massachusetts General Hospital in Boston and Robert Brown, formerly at Mass General and now at the University of Massachusetts School of Medicine in Worcester. Brown was the director of the MDA/ALS Center at Mass General prior to his recent move to the University of Massachusetts, and has received MDA funding for ALS research.

The team also included Guy Rouleau at the University of Montreal, the recipient of several MDA grants for research in ALS genetics.

The U.K. and Australian team was coordinated by Christopher Shaw at King’s College London and the Institute of Psychiatry in London. First author Caroline Vance is also at both those institutions.

The North American group identified 13 mutations in the gene for the FUS protein in 17 familial ALS families. The U.K. and Australian group found three ALS-causing mutations in the FUS gene in nine families. Two of the mutations they identified were also found in the North American patients.

The FUS (“fused in sarcoma”) protein is thought to be involved in DNA repair, the regulation of transcription from DNA to the related compound RNA, which becomes the genetic recipe for the synthesis of each protein; further RNA processing; and movement of RNA from the cell nucleus to the main part of the cell (the cytoplasm). Its name is derived from a previous identification of its role in a type of cancer called sarcoma.

Normally, FUS protein molecules stay in the nucleus and don’t clump together. However, FUS protein molecules made from mutated FUS genes are more likely to be located in the cytoplasm, where they tend to clump together. This type of clumping (aggregation) has been correlated with degeneration of nerve cells in ALS and other conditions. In fact, the clumps are similar in appearance to those found in another rare form of familial ALS that’s caused by mutations in the TDP43 gene.

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Angiogenin gene mutation appears to cause ALS in large Dutch family

Researchers in the Netherlands and Canada have identified a mutation in the gene for the angiogenin protein as the cause of ALS in a large, multigenerational Dutch family. The protein is thought to play a role in helping outgrowths from nerve cells follow the correct pathways.

Leonard van den Berg at University Medical Center in Utrecht, Netherlands, and colleagues, who published their findings in the Jan. 20, 2009, issue of Neurology, analyzed DNA samples from 44 of 62 family members, five of whom had ALS symptoms. All five carried a specific mutation in the angiogenin gene. One showed symptoms of ALS, frontotemporal dementia (cognitive dysfunction) and Parkinsonism (a movement disorder), which the investigators say suggests the angiogenin gene may be involved in all three conditions.

An additional 10 family members carried the gene but appeared unaffected. One carrier was 75 years old and without ALS symptoms, but all the rest were younger than 50, leading researchers to conclude that the carriers might not have reached the age when symptoms would appear. Another probable carrier died at age 50 of cardiovascular disease.

The mutation was not found in 39 unrelated people with familial ALS, nor in 275 unrelated, healthy people.

The same mutation has been seen in three cases of ALS in which there was no family history (sporadic ALS), and other mutations in the angiogenin gene have been seen in both familial and sporadic cases. However, this is the first clear correlation of a specific mutation associated with the disease in several members of the same family.

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FIG4 gene variants implicated as ALS risk factors

Variations in the gene for the FIG4 protein probably can be added to the list of identified risk factors for the development of ALS, say researchers at several academic centers in Michigan and Massachusetts.

Miriam Meisler, in the Department of Human Genetics at the University of Michigan in Ann Arbor, with colleagues at that institution and others, analyzed DNA samples from 473 people with ALS or a related disorder called primary lateral sclerosis (PLS). The study included 364 patients with sporadic (nonfamilial) ALS or PLS and 109 with familial ALS or PLS.

Each identified variant in the FIG4 gene suspected of being disease-related was checked in at least 395 unaffected (“control”) DNA subjects to see whether it was also present in them. Most variants were tested in 558 unaffected people.

In nine of the 473 people with ALS or PLS, investigators found FIG4 DNA variants that were not present in the control group. Six of the nine variants impaired the function of the FIG4 gene.

FIG4 is thought to synthesize a molecular “tag” that directs membrane-enclosed, substance-carrying sacs called vesicles to their proper targets inside cells. It also may play a role in moving substances through the long fibers (axons) of nerve cells. Disruption of this type of transport could be deadly to these cells.

Chaperone Protein diagram
Arimoclomol stimulates production of chaperone proteins, which attempt to maintain quality control by repairing damaged protein molecules; or, if they can’t, tag them for a cellular disposal system.

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New arimoclomol study opens for people with SOD1 ALS

Arimoclomol, a small molecule developed by the Los Angeles biopharmaceutical company CytRx, increases levels of proteins known as “chaperones,” which may improve a cell’s ability to survive certain types of stress, such as misfolded protein molecules.

In a trial of approximately 80 people with ALS conducted in 2005 and 2006, arimoclomol was found to be safe and well tolerated at three dosage levels tested (25, 50 or 100 milligrams three times a day for 12 weeks).

A trial of arimoclomol at 400 milligrams three times a day in people with familial and nonfamilial (sporadic) ALS was planned for early 2008. However, the U.S. Food and Drug Administration (FDA) placed the trial on hold on Jan. 22, 2008, because of concerning data from toxicity studies in animals. That trial remains on hold as of March 2009.

Now, a new study will test the drug at 100 milligrams three times daily, will incorporate extensive safety measures, and will include only patients with SOD1-related familial ALS.

The principal investigators are Michael Benatar, co-director of the MDA clinic at Emory University in Atlanta, and Merit Cudkowicz, who directs the MDA/ALS Center at Massachusetts General Hospital in Boston.

The investigators say they believe it’s possible that arimoclomol will be more effective in people with SOD1 ALS than with other types of ALS, since it was effective in a mouse model of SOD1 ALS.

They’re seeking 80 people with familial ALS who either know they have an SOD1 mutation or are willing to undergo genetic testing to find out; are willing to travel to Atlanta or Boston twice, as well as undergo several in-home or telephone assessments; and meet other study criteria.

At Emory, contact Michael Benatar at or Cathy Raiser at At Mass General, contact Merit Cudkowicz at or Darlene Pulley at dpulley@partners.

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Investigators seek to understand how SOD1 ALS develops

Michael Benatar, who co-directs the MDA clinic at Emory University in Atlanta, is the principal investigator on an MDA-supported study that seeks to identify people with familial (inherited) ALS due to a mutation in the SOD1 gene, before they develop symptoms. (SOD1 ALS accounts for about 20 percent of familial cases of the disease, or about 2 percent of all cases.)

The goals are to better understand the early manifestations of the disease and the factors that cause some people to develop it earlier than others; and perhaps ultimately to undertake a clinical trial in which people at high risk for familial ALS are treated in advance of symptoms.

The researchers are seeking at least 30 people from families in which at least two people have had ALS, or who have a parent, sibling or child with ALS; who have no ALS symptoms themselves; and who are willing to travel to Emory University in Atlanta on an annual basis. Genetics testing will be part of the study, but participants can choose whether or not they want to learn the results.

Contact Sue Gronka at or (888) 413-9315.

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Modafinil may help combat fatigue in ALS

Study results reported in the March 2009 issue of Muscle & Nerve indicate that modafinil (brand name Provigil) “may be a promising intervention for fatigue in ALS patients.” Fatigue and daytime sleepiness often accompany ALS.

Hiroshi Mitsumoto, director of the Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University Medical Center in New York, where the study was based, received MDA support to conduct it.

Modafinil has U.S. Food and Drug Administration (FDA) approval for the treatment of adults with excessive sleepiness related to the neurologic disorder narcolepsy, obstructive sleep apnea syndrome and shift-work sleep disorder.

The trial found 19 of 25 (76 percent) of study participants randomly assigned to receive modafinil for four weeks were judged to be “responders” to the medication. Only one of seven (14 percent) assigned to a placebo (inert, look-alike substance) was judged to be a responder.

Participants were assessed using the Clinical Global Impressions Improvement Scale, a standardized assessment tool that uses scores from 1 (very much improved) to 7 (very much worse), as compared to baseline. This global assessment is based on all available data, including the judgment of the clinician and self-reports of the patients.

Although “encouraging,” Mitsumoto cautions that the study was small and a larger study is needed to confirm results.

An earlier, 15-person study, conducted by Greg Carter and Michael Weiss, co-directors of the MDA/ALS Center at the University of Washington-Seattle, had shown modafinil was well tolerated by ALS patients and that it improved measures of daytime sleepiness. (See “Modafinil may help with staying awake,” February-March 2005.)

For more on fatigue and modafinil in ALS, see “Fighting Off Fatigue.”

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FDA to allow testing of Iplex in ALS

In a change to an earlier decision, the U.S. Food and Drug Administration (FDA) announced March 10 that it would approve human clinical testing of the experimental drug Iplex in ALS. The drug is developed by Insmed of Richmond, Va.

man in clinic
Several clinical trials are under way to test therapies that may slow the disease process or improve quality of life.

Earlier this year, the FDA had said it would allow the use of Iplex only on a “compassionate use” basis, for specific ALS patients whose doctors had made requests to the FDA. (Such requests will continue to be honored if they were received by the agency by March 6. Later applicants will only be able to receive Iplex through a clinical trial.)

Iplex is a combination of insulin-like growth factor 1 (IGF1) and IGF1 binding protein 3a. IGFI protein has some neuroprotective properties, but has not shown efficacy in three trials in people with ALS.

The drug, approved for use in children with certain types of growth failure, is being tested in myotonic muscular dystrophy, with MDA support. Although there is no evidence to indicate it is effective in ALS, data from Italy (recently made available to the FDA) suggest it is probably reasonably safe in this disease.

For details about the planned trial, contact Insmed at (804) 565-3083 or

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Ceftriaxone trial finds drug is safe, reaches spinal fluid

The first two stages of the clinical trial of ceftriaxone in ALS are now complete. This drug was selected for study in ALS because of evidence that it may increase clearance of the potentially toxic substance glutamate from the area around nerve cells.

The aim of stage 1 was to determine the pharmacokinetics (how cells and tissues interact with the drug) of ceftriaxone at 2 grams and 4 grams per day. The goal of stage 2 was to determine the safety and tolerability of ceftriaxone over 20 weeks.

Sufficient concentrations of ceftriaxone in the targeted tissue, the fluid around the spinal cord (cerebrospinal fluid) were achieved, and both dosages were safe and tolerable.

The efficacy portion of the study, now getting under way, will measure the effects of ceftriaxone on survival, scores on the ALS Functional Rating Scale, strength and breathing function.

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One lithium study closes, and a new one opens

As of late January 2009, a multicenter, MDA-supported trial of lithium in ALS completed its enrollment and closed to further recruitment.

For safety reasons, the investigators chose 450 milligrams per day as the highest dosage level in this trial. The safety of this drug in patients with ALS is still unclear, they say, and they’re gathering data on side effects. In the meantime, they advise that lithium interacts with many other drugs and shouldn’t be taken by ALS patients outside a study.

Safety and efficacy of lithium in ALS will be assessed after trial participants have been on the drug for one year.

A separate multicenter study of lithium and riluzole in ALS, supported by the National Institutes of Health, is now open at 37 centers in the United States and Canada. Neurologist and MDA research grantee Merit Cudkowicz, who directs the MDA/ALS Center at Massachusetts General Hospital in Boston, is a principal investigator, as is Swati Aggarwal, at the same institution. Contact Liz Simpson at (617) 726-3430 or

ALS patients taking lithium have documented their experiences on Patients Like Me.

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Scientists create ALS model from stem cells

Investigators at the David Geffen School of Medicine of the University of California-Los Angeles and the University of Rochester (N.Y.) Medical Center have created models of ALS disease progression in nerve cells derived from human embryonic stem cells. They gave these cells mutated SOD1 genes, a known cause of familial ALS.

Martina Wiedau-Pazos at UCLA and colleagues, who published their findings in the March-April issue of Disease Models & Mechanisms, developed functional motor neurons (the muscle-controlling nerve cells that die in ALS) and gave each cell a normal SOD1 gene or an SOD1 gene with a mutation known to cause human disease.

They tested SOD1 genes with the A4V mutation, known to cause a rapid and severe form of human ALS; the I113T mutation, known to cause milder and more slowly progressive ALS in humans; and the G93A mutation, which causes ALS of intermediate severity and progression rate.

Investigators found that all three mutations caused the cells to develop shorter nerve fibers than the fibers seen with the normal SOD1-bearing motor neurons, and the cells with the mutated SOD1 genes didn’t survive as long as the ones with the normal SOD1 genes.

Interestingly, the effect on cell survival and fiber shortening was most severe in the motor neurons with the A4V SOD2 mutation, least severe in the cells with the I113T mutation, and in between in those with the G93A mutation. These results correspond with reports of disease severity associated with these mutations in patients.

Wiedau-Pazos has had MDA funding for closely related work, and MDA is pursuing the use of stem cells as investigative and therapeutic tools in ALS through California Stem Cell in Irvine, Calif., and the ALS Therapy Development Institute in Cambridge, Mass.

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Margaret Wahl
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