ALS Research Roundup July-Aug. 2009

by ALSN Staff on Wed, 2009-07-01 13:32
Article Highlights:

Updates on research, clinical trails and studies as of June 2009

This article presents updates on research, clinical trials and studies in ALS as of June 2009: ceftriaxone, pyrimethamine, tamoxifen, brain-computer interface, gene variants, PLS, spinal cord barriers, ALS Newsmagazine

Ceftriaxone trial enters third stage

Ceftriaxone, administered intravenously, may help clear away potentially toxic glutamate.

A trial of intravenous ceftriaxone in ALS has now entered its third stage and is enrolling participants at approximately 50 U.S. and four Canadian medical centers. The study is supported by the National Institutes of Health.

Ceftriaxone is marketed as an antibiotic to treat infections. Recently, laboratory screening showed it might also increase the amount of a protein called a glutamate transporter, which helps clear glutamate from the area around nerve cells. Glutamate, though necessary to transmit signals in the nervous system, can be toxic in large amounts.

The first stage of the study, which has completed enrollment, is determining whether ceftriaxone enters the fluid surrounding the spinal cord in high enough amounts to be of possible benefit. The second stage, which also has completed enrollment, is looking at safety and side effects of ceftriaxone administered for at least 20 weeks.

The third stage, which began enrolling participants this spring, will determine whether the drug prolongs survival or slows functional decline in ALS.

The study has a “nonstop, adaptive design,” meaning interim analyses of data regarding safety, tolerability and distribution of the drug in the body are reviewed by a monitoring board and used to determine whether the investigators can proceed to the next stage. However, the data themselves aren’t released to the investigators or anyone else until the entire study has been completed.

For more information, contact Fran Murphy at Massachusetts General Hospital in Boston at (617) 643-3980 or To see a complete list of study sites, go to MDA Research and search under “ceftriaxone.”

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Antimalarial drug under study in FALS

Dale Lange, who directs the MDA clinic at Joan and Sanford I. Weill Medical College of Cornell University, New York, is set to begin an MDA-supported phase 1 trial to study the effects of pyrimethamine in people with FALS, or familial (inherited) ALS due to a mutation in the SOD1 gene. (SOD1 ALS accounts for about 20 percent of familial ALS, or about 2 percent of all cases of ALS.)

Enrolling in clinical trials and studies doesn't necessarily benefit the participant, but it's crucial for moving research in ALS from the laboratory to the community. To view active and completed studies in ALS, see Clinical Trials & Studies at

Marketed under the brand name Daraprim, pyrimethamine is approved by the U.S. Food and Drug Administration for the treatment of malaria and toxoplasmosis, both parasitic infections.

Evidence from animal studies indicates the medication may reduce the amount of toxic mutant SOD1 molecules. A number of patients with ALS in an earlier pilot study also experienced a reduction in their SOD1 levels while taking pyrimethamine. It’s thought that reducing levels of the mutant SOD1 protein may alleviate the disease.

The researchers will study the drug in 40 people with mild to moderate familial ALS and SOD1 mutations. The goals are to determine whether pyrimethamine is safe and tolerated, and whether it can lower the amount of SOD1 in immune system blood cells known as lymphocytes.

Contact Mona Shahbazi at (212) 774-2361, or for more information.

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Tamoxifen may have benefit

The drug tamoxifen (Nolvadex), approved for the treatment of breast cancer, has shown possible beneficial effects on survival and respiratory function in ALS. There was, however, no increase in strength or change in the rate of decline on the ALS Functional Rating Scale. The results are considered preliminary.

Tamoxifen is a “selective estrogen receptor modulator,” a drug that mimics the effects of the female hormone estrogen in some tissues and blocks them in others.

Neurologist Benjamin Brooks was the principal investigator on this study, which was funded in part by MDA. Brooks said the tamoxifen trial results are now being prepared for publication. He also noted that further studies of tamoxifen or a similar drug called raloxifene (Evista) are in the planning stage.

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Brain-computer interface research continues

Scientists are exploring how best to enable a person to control a computer by thoughts. The BrainGate device utilizes electrodes that are implanted in the motor cortex, a part of the brain that controls movement. Other experimental devices sit on the brain’s surface or the scalp.

BrainGate, an investigational “brain-computer interface” technology being developed to detect brain signals generated by thoughts and allow people with paralysis to use those signals to control assistive devices, is now undergoing further testing in a second clinical trial.

The BrainGate 2 pilot clinical is funded by the National Institutes of Health, the U.S. Department of Veterans Affairs and philanthropic sources. It’s taking place at Massachusetts General Hospital (MGH) in Boston, in close collaboration with an interdisciplinary team of researchers from MGH and Brown University in Providence, R.I.

For more about BrainGate, including a video and information about participating in the research, see BrainGate; or contact investigator Leigh Hochberg at (617) 726-4218 or

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KIFAP3 gene variant prolongs survival

A variant version of the gene for a protein known as KIFAP3 has been found to increase survival time in people with sporadic (nonfamilial) ALS by an average of 14 months.

Researchers found a variant in the gene for the KIFAP3 protein that correlated with longer survival time.

The findings of John Landers at the University of Massachusetts Medical School in Worcester, with colleagues from institutions around the world, were published online May 18, 2009, in Proceedings of the National Academy of Sciences. MDA supported Orla Hardiman and Simon Cronin at the Royal College of Surgeons in Dublin, Ireland, for this work.

The researchers conducted a “genome-wide association” study, in which they scanned the entire genome (set of genes) of study participants, looking for any association of gene variants with ALS risk, survival time or other ALS-related factors.

They analyzed the genomes of 1,821 people with sporadic ALS and 2,258 without the disease from the United States and Europe. Included in the analysis was the survival time of 1,014 people who had died of ALS.

The researchers found a single variant, in the gene for KIFAP3 (kinesin family-associated protein 3), that significantly correlated with ALS survival time.

Human chromosomes are found in pairs, and people with ALS who had the survival-enhancing KIFAP3 gene variant on both copies of chromosome 1 survived an average of 14 months longer than people with this variant on only one chromosome 1 or on neither chromosome 1.

None of the variant forms of any genes in this study were significantly associated with ALS risk, site of onset or age of onset.

The variant in the KIFAP3 gene is one that reduces output from the gene, so that less KIFAP3 protein is produced. The investigators say they don’t know why having less KIFAP3 protein would prolong survival in ALS, but they believe, based on the normal function of this protein, that its reduction may reduce transport of toxic molecules inside nerve fibers. They note that KIFAP3 levels are increased early in the disease process in mice with an ALS-like disease due to mutated SOD1 genes.

“Few genetic factors that modify ALS survival are reported,” the authors write, noting that none have been identified in previous genome-wide association studies in ALS. “The identification of KIFAP3 as a determinant of progression rate of sporadic ALS is therefore promising.”

They note that lowering KIFAP3 production or changing the interactions of this protein with other proteins might be worth investigating as an ALS therapy.

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If ALS hasn't developed in four years, full disease is less likely

Full-blown ALS usually makes itself known within four years of the first symptoms, found an MDA-supported study published June 2, 2009, in Neurology.

A diagnosis of ALS requires signs that both upper (brain) and lower (brainstem and spinal cord) motor neurons are degenerating. When only the upper motor neurons are lost, the disease is often called “primary lateral sclerosis,” or PLS. This disease, which is rarer than ALS, allows for a higher level of functioning and longer survival time than ALS. (See “When It’s Almost ALS, Will the Disease Progress?” June 2007.)

Upper motor neuron loss is associated with muscle spasticity, while lower motor neuron loss causes weakness or paralysis.

Upper motor neurons are nerve cells that send signals to lower motor neurons, which in turn send signals to muscles.

When lower motor neurons degenerate, the main effects are weakness or paralysis in the muscles they control. These can include limb and trunk muscles, respiratory muscles (such as the diaphragm), and muscles associated with chewing, swallowing and speaking. Muscle atrophy (shrinkage) and weight loss are also effects of lower motor neuron degeneration.

When upper motor neurons are lost, the main effects are spasticity (tightness) in muscles that continue to receive input from lower motor neurons alone.

Neurologist Paul Gordon and colleagues at the Eleanor and Lou Gehrig MDA/ALS Center at Columbia University in New York reviewed the records of 34 patients with signs of dysfunction of upper motor neurons, lower motor neurons, or both, who visited the center between 1984 and 2007.

They found a diagnosis of PLS with a very slow rate of progression and prolonged high-level functioning applied only to patients who did not develop any signs of lower motor neuron dysfunction.

They found patients whose disease was mostly confined to the upper motor neurons but who developed even subtle lower motor neuron abnormalities had a shorter survival time than those whose disease remained confined to the upper motor neurons. Even if lower motor neuron signs were initially subtle, patients who developed them eventually showed functional deterioration similar to that of typical ALS.

Signs of lower motor neuron abnormalities include weakness, diminished respiratory capacity, weight loss, and abnormalities of nerve-signal transmission detected on an electromyogram (EMG).

Most (77 percent) of patients who had only upper motor neuron degeneration when first seen at the center but who later developed lower motor neuron signs did so by the fourth year after the first symptoms began.

The Columbia researchers suggest that, if after four years, signs of lower motor neuron degeneration have not yet been seen, a diagnosis of PLS can be made, although they caution that a minority of these patients still develop ALS later on.

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Barriers in spinal cord appear leaky in ALS

Proteins that keep large molecules from moving freely across blood-vessel walls in the spinal cord appear to be deficient in people with ALS, MDA-supported researchers say. They don’t yet know, however, whether a lower-than-normal level of some of these so-called “tight junction” proteins, is helpful or harmful in the disease process.

Neurologist and MDA grantee Stanley Appel, who directs the MDA/ALS Center at Methodist Neurological Institute in Houston, and colleagues, published their findings in the May 5, 2009, issue of the journal Neurology.

The researchers measured levels of messenger RNA, the final genetic instructions from which a cell makes a protein, in spinal cord samples from 30 people with sporadic (nonfamilial) ALS, four with familial ALS and a control group of 16 people with no neurodegenerative disease.

They found the messenger RNA for the tight junction protein called zona occludens 1 (ZO1) was lower in lumbar spinal cord tissue in people with sporadic ALS compared to tissue from the control group. There was no difference in the RNA for ZO1 in the four familial ALS samples compared to the control group.

Messenger RNA levels for another tight junction protein, occludin, were lower in lumbar spinal cord samples from people with familial ALS than they were in samples from the control group, but there was no difference between the sporadic ALS samples and control group samples.

RNA levels for a third tight junction protein were the same in the ALS samples as a whole and the control samples.

The researchers note that previous studies have suggested that the vascular barrier between the bloodstream and the spinal cord, known as the “blood-spinal cord barrier,” is leakier than normal in ALS, and they say this study adds further support to that evidence.

They say the leakiness could lead to the entry of toxic molecules into the spinal cord and contribute to the nerve-cell damage that characterizes ALS.

Conversely, they note, the enhanced permeability could allow the entry of immune-system cells that have been associated with protection of nerve cells in this disease.

If the first scenario proves to be the case, they say, then preserving the integrity of the blood-spinal cord barrier may represent a target for therapeutic development.

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ALS Newsmagazine to become bimonthly publication

As it manages its resources in this troubled economy, MDA has made the difficult decision to cut back publication of the MDA ALS Newsmagazine from 10 to 6 issues a year. Beginning with the September 2009 issue, the magazine will be published every other month.

Up-to-the minute news on ALS research and living with ALS always can be found on the MDA ALS Division Web pages.

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