Research Roundup updates as of May 2007:
‘Toxic neighbors’ likely kill nerve cells, at least in SOD1-caused ALS
Nervous system support cells known as astrocytes and nervous system immune cells called microglia appear to play a role in whether motor neurons in the spinal cord live or die, at least in one form of genetic ALS. Motor neurons (nerve cells that control muscle activity) degenerate in all forms of ALS.
|Two new studies suggest that motor neurons, even when healthy, can be killed by toxic support cells, and that ALS-affected motor neurons can trigger the immune system to attack them.
Investigators at Columbia University in New York and Harvard University in Cambridge, Mass., demonstrated in laboratory dishes that astrocytes, when carrying an ALS-causing genetic mutation in the SOD1 gene, secrete an unknown toxic substance that kills healthy motor neurons.
The two groups announced their findings independently April 15 online in Nature Neuroscience. MDA research grantee Serge Przedborski was part of the Columbia team.
Przedborski and colleagues found that motor neurons were specifically vulnerable.
“Only the motor neurons seem to succumb, even though you have different cells in the environment,” Przedborski said. “We concluded that there seems to be a selective coupling between astrocytes that have a toxic effect and motor neurons as the primary recipients of this toxic effect.”
In another set of experiments, Don Cleveland and colleagues at the University of California-San Diego, including MDA grantee Severine Boillee, built on their previous findings about the role of microglia in the death of motor neurons (see “Outside Agitators,” February 2007), also using a laboratory model of SOD1-caused ALS.
In an April 27 online publication in Proceedings of the National Academy of Sciences, this group announced that ALS-affected motor neurons, taken from mice carrying a variety of ALS-causing mutations in the SOD1 gene, produce proteins normally made by cells in the immune system. These proteins, which together are called the “classical complement pathway,” probably incite attacks on motor neurons by surrounding microglia, the authors say.
Taken together, these findings lead to “good news, bad news” conclusions for ALS research. The good news is that transplanting healthy stem cells that become astrocytes or microglia might slow the disease process by providing neurons with a more supportive environment. (These cells are more practical for transplantation than are motor neuron stem cells.)
The bad news is that, if stem cells destined to become motor neurons were transplanted into a spinal cord harboring abnormal astrocytes or activated microglia, they probably wouldn’t survive.
Neither Przedborski nor Cleveland could say whether these findings apply to the approximately 98 percent of human ALS cases that aren’t related to mutations in the SOD1 gene. However, some evidence supports the idea that the differences between SOD1-related and other types of ALS occur only at the very beginning of the disease and then converge.
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|Paul Gordon co-director of Eleanor and Lou Gehrig MDA/ALS Research Center, was the principal investigator on the minocycline trial.
Minocycline doesn’t slow ALS progression
Disappointing results of a nine-month trial of minocycline, an antibiotic in the tetracycline family thought to reduce inflammation and counteract cell death, were announced May 1 at the American Academy of Neurology (AAN) annual meeting in Boston.
The trial, which had MDA funding, tested high-dose minocycline (400 milligrams per day) versus a placebo (inert substance) in 412 people at 31 U.S. centers. The drug failed to slow the decline in functional outcome measures and in some patients worsened measurable outcomes.
Valerie Cwik, medical director at MDA, said people who are taking minocycline should contact their physicians to discuss discontinuing it.
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Sodium phenylbutyrate passes safety trial
Also at the American Academy of Neurology meeting, Merit Cudkowicz of Massachusetts General Hospital in Boston announced that a safety trial of sodium phenylbutyrate showed the drug was safe and that the majority of participants tolerated a dosage of up to 15 grams a day. More than half of the participants tolerated the maximum dosage of 21 grams daily.
|Merit Cudkowicz at Massachusetts General Hospital in Boston Received MDA support for the sodium phenylbutyrate trial.
Cudkowicz received support from MDA and the U.S. Department of Veterans Affairs to conduct a safety trial of this drug, which has shown promise in ALS-affected mice. Sodium phenylbutrate is also in development for spinal muscular atrophy and Huntington’s disease.
Even at the lowest dosage, 9 grams, the investigators saw an increase in a chemical process called histone acetylation, a target of the therapy. The process opens DNA instructions that can otherwise be “unreadable” by cells.
The trial included 40 ALS-affected participants, who each took sodium phenylbutyrate for 20 weeks. There were no unexpected adverse events. Cudkowicz said the next step, pending regulatory approvals, will be an efficacy study.
Even though sodium phenylbutrate is a marketed drug and prescribed for children with certain metabolic abnormalities, the U.S. Food and Drug Administration has requested animal safety studies before giving regulatory approval for tests of drug efficacy in patients.
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