Research Roundup updates as of February 2008
MDA to fast-track lithium trial
|A small trial has suggested that lithium carbonate may dramatically slow ALS progression. Larger trials will be needed to confirm these results.
An MDA-supported clinical trial of lithium in ALS is being planned, after a 44-person study in Italy showed the drug delayed progression of the disease compared to a placebo (inactive substance).
“Although the number of study participants was small, the results are very intriguing,” said neurologist Valerie Cwik, MDA’s medical director and vice president of research. “MDA already is working with researchers in the United States to launch a larger, confirmatory study as quickly as possible.”
In the Italian study, 16 trial participants were randomly selected to receive riluzole plus two daily doses of lithium carbonate. The remaining 28 participants were randomly assigned to receive riluzole only. The two groups were matched for pulmonary function and percentage of people with bulbar-onset ALS.
After 15 months, about 30 percent of the patients who took riluzole alone had died, while all those receiving riluzole plus lithium had survived. The disease had progressed markedly in the riluzole-only group, but very slowly in the riluzole-plus-lithium group.
Francesco Fornai at the University of Pisa (Italy), with colleagues at other Italian institutions, announced the results online Feb. 4 in Proceedings of the National Academy of Sciences.
Lithium should be taken under a doctor’s supervision, with frequent monitoring of blood levels to check for toxicity.
[Note: Once MDA begins recruiting clinical trial participants, it will be announced in the newsmagazine and on the MDA ALS Web site.]
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Arimoclomol trial on hold
On Jan. 22, the U.S. Food and Drug Administration (FDA) told CytRx Corp. not to proceed with the phase 3 trial of arimoclomol in ALS until the agency could further analyze previously completed animal studies with the drug. For more, see www.cytrx.com.
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Looking outside nerve cells for causes of ALS
Recent work by two scientific teams extends earlier findings that, while muscle-controlling nerve cells (motor neurons) are lost in ALS, other cells in the nervous system probably also play a role.
|New research confirms that non-nerve cells in the nervous system are involved in at least one form of ALS. These might be easier than nerve cells to replace or support.
Investigators at the University of Iowa led by John Engelhardt have found that an abnormal protein that underlies a familial form of ALS can cause damage apart from anything it’s doing in motor neurons.
Engelhardt and colleagues found that in immune-system cells of the nervous system called microglia, the SOD1 protein normally interacts with a protein called RAC1. The SOD1-RAC1 complex then triggers a third protein, NOX2, to produce needed but potentially dangerous molecules called reactive oxygen species, or ROS, which can leak out and damage neighboring cells. They published their results online in the Journal of Clinical Investigation Jan. 24.
Normally, the SOD1-RAC1-NOX2 combination causes ROS production, but when these rise to a certain level, SOD1 and RAC1 separate, and ROS production stops.
“In essence, SOD1 acts like a thermostat, which senses ROS and tells the NOX2 complex when to stop producing ROS,” Engelhardt says.
But in mice with mutated SOD1 genes, SOD1 doesn’t separate from RAC1. The thermostat is broken, the furnace stays on, and toxic levels of ROS damage nearby cells, such as motor neurons.
When the scientists gave the chemical apocynin to 2-week-old mice with an SOD1 gene mutation, the animals had a more slowly progressing ALS-like disease and ended up with more spinal cord motor neurons than untreated mice did. Apocynin is a small chemical found in certain plants that interferes with production of ROS molecules by “unplugging” the molecular furnace. The mice received it in their drinking water.
A complementary study by scientists in the United States and Japan suggests targeting cells called astrocytes also might be beneficial.
Like microglia, astrocytes are in the nervous system but aren’t nerve cells (neurons). They normally support neurons by keeping their environment nontoxic.
Don Cleveland at the University of California-San Diego led a research team that included MDA grantee Severine Boillee at UCSD and published its findings online Feb. 3 in Nature Neuroscience.
When these investigators bred mice with diminished production of mutated SOD1 in their astrocytes alone, they observed sharply slowed disease progression compared to progression in mice that produced high levels of mutated SOD1 in these cells.
In areas where astrocyte-produced mutated SOD1 was high, microglia revved up production of toxic compounds.
In 2006, Boillee and colleagues showed that decreasing mutated SOD1 protein levels in microglia also sharply slowed disease progression in mice.
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Genes involved in axon guidance implicated in ALS
Investigators at the Mayo Clinic in Rochester, Minn., and the University of Miami have applied a new approach to studying genetic variants that may play a role in ALS and say genes involved in “axon guidance” are significantly different in people with ALS, as compared to healthy subjects.
Axon guidance refers to the process by which the brain and spinal cord are “wired” during fetal development and the process by which this wiring is maintained and repaired throughout life.
|Axons (nerve fibers) connect nerve cells to muscle fibers and to other nerve cells. They need maintenance throughout life.
Two previous analyses, called “whole-genome association” studies, compared all the DNA of a group of people with ALS to all the DNA of a group of people without ALS. The first study, which was MDA-supported and conducted by the Translational Genomics Research Institute in Phoenix, found some 50 variants that might contribute to ALS, including one that was particularly significant. (The function of the gene in which this variant was found has not yet been identified.)
The second study, conducted by the National Institutes of Health, found no significant DNA differences between the ALS-affected and unaffected groups.
In this new analysis, Demetrius Maraganore at the Mayo Clinic and colleagues, who published their findings in the January issue of PLoS One, hypothesized that genes involved in axon guidance might have ALS-associated variant DNA sequences.
When they looked at 128 genes already identified as being in the axon-guidance pathway and compared them as a group in the ALS-affected and unaffected study participants, they found a significant difference in the two types of participants.
MDA is talking with the Mayo Clinic group about pursuing this line of research.
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XMRV not an ALS contributor
The so-called xenotropic MuLV-related virus (XMRV) has been eliminated as a contributor to ALS, according to Jeremy Garson at University College London (UK) Centre for Virology and colleagues.
The research team, which announced the findings in the Jan. 22 issue of Neurology, included Robert Brown, director of the MDA/ALS Center at Massachusetts General Hospital in Boston. When they searched for genetic material from XMRV in ALS patients’ blood, they found none.
The investigators say their results show that XMRV is highly unlikely to explain elevated levels of activity of the viral enzyme reverse transcriptase seen in ALS patients’ blood. They say they’ll continue to search for other viruses.
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