Research Roundup updates as of December 2007
Some 750 conferees, mostly ALS clinical and scientific experts, gathered in Toronto Dec. 1-3 for the 18th International Symposium on ALS/MND (Motor Neuron Disease), sponsored by the British Motor Neurone Disease Association.
Michael Strong, a professor of neurology at the University of Western Ontario, presented the increasingly compelling evidence that ALS is not one disease, but many.
The evidence includes the wide range of survival times; variability in the parts of the brain affected, including nonmotor areas in some people but not others; and the lack of a single genetic factor leading to ALS.
The failure of mouse studies to predict human responses to experimental treatments may be due to the lack of a single cause of ALS among human patients, compared to the uniformity of disease causation (usually, a mutation in the SOD1 gene) in lab mice.
ALS patients typically are grouped by whether their disease is familial or sporadic, by the site of symptom onset and by rate of disease progression. However, these categories aren’t sufficient to reflect the wide variation seen in ALS.
Results of several specific trials were presented, as follows.
Large-scale minocycline trial showed drug is harmful in ALS
|Paul Gordon, until recently a co-director of an MDA/ALS Center in New York, presented information on two drug trials.
Paul Gordon, until recently an assistant professor of neurology at Columbia University in New York and a co-director at the Eleanor and Lou Gehrig MDA/ALS Center at Columbia, presented the results of a 412-person, phase 3 trial of minocycline, a drug that had shown promise in ALS-affected rodents and in phase 1 and phase 2 studies in patients. (Gordon is now at the Hôpital Pitié Salpêtrière in Paris.)
Minocycline is an antibiotic used to treat certain types of infections. It also has the ability to prevent a cell “suicide” program (apoptosis) and to dampen inflammation.
Participants at 31 U.S. centers were randomly assigned to either minocycline in escalating doses up to 400 milligrams per day, or to a placebo, for nine months, following a four-month lead-in phase during which patients’ untreated rate of decline in the ALS Functional Rating Scale (ALSFRS) was observed.
ALSFRS scores deteriorated 25 percent faster in the minocycline group than in the placebo group, although survival was the same in the two groups. The rate of ALSFRS decline wasn’t dependent on the dose of minocycline, or if people also were taking riluzole (Rilutek).
Gordon said these disappointing results demonstrate the need to improve both the reliability of animal studies in predicting human responses to treatments, and the ability to use early-phase trials to select potentially beneficial compounds and eliminate useless or harmful ones.
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Celecoxib and creatine combination may warrant further testing
Gordon also reported on a trial conducted at Columbia to compare two drug combinations against a historical control group (a similar group of ALS patients, previously observed and not treated with either combination).
Patients were randomly assigned to take either creatine plus minocycline or creatine plus celecoxib (Celebrex) for six months and were evaluated using the ALSFRS each month.
Of 60 people, 58 completed the trial. Average ALSFRS decline in the creatine plus celecoxib group was 5.27 units; in the creatine plus minocycline group, 6.47 units; and in the historical control group, 5.82 units.
The creatine-celecoxib combination was selected for further study.
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Ritonavir eliminated, but hydroxyurea may be worth closer look
Catherine Lomen-Hoerth, who directs an MDA/ALS center at the University of California at San Francisco, reported on phase 1 trials of Ritonavir, a medication used for HIV/AIDS, and hydroxyurea.
Ritonavir reduces levels of two compounds involved in cellular waste disposal that are elevated in ALS. Hydroxyurea, which is used to treat leukemia, may prevent damage from astrocytes and microglia, two types of nervous-system support cells. Anecdotal reports from three people with ALS suggested possible benefit.
Participants were randomly assigned to receive either low-dose Ritonavir, high-dose Ritonavir, hydroxyurea or a placebo for six months, followed by an additional six months of observation.
Among 24 enrolled patients, investigators found no significant improvements over placebo among the low- and high-dose Ritonavir groups. However, the hydroxyurea group did slightly better than the placebo group on tests of strength and on the ALS Functional Rating Scale (ALSFRS), and their respiratory scores were better than the placebo group.
Lomen-Hoerth said they’re considering a phase 2 study of hydroxyurea.
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Dutch study warns against Chinese stem-cell treatments
Leonard Van Den Berg, a neurologist at University Medical Centre in Utrecht, Netherlands, reported on followup studies of patients who went to China for treatment with a type of stem cell found in human fetal nasal lining (olfactory ensheathing cells, or OECs).
At Beijing West Hill Hospital and Rehabilitation Center, OECs are injected into the brains of ALS patients, at a cost of approximately $25,000.
A Dutch study followed 12 patients who went to Beijing. Seven reported very short-term improvement in functioning or an increase in strength immediately after the injections, lasting less than a day. Three saw no change, and two said they deteriorated.
ALSFRS scores, respiratory measurements and strength tests resumed a downward course in all cases. Of the 10 patients who later died, median survival time was 2.9 years. One person developed a serious blood clot, and another developed pneumonia.
Van Den Berg recommended that people not seek stem-cell treatments in Beijing. He also reported that the West Hill center has since closed, because the Chinese government considered it too “mercantile.”
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Strenuous lifestyle may increase ALS susceptibility
Agnes Gonzalez, a research nurse at an ALS center in Montpellier, France, described her team’s study, in which preliminary results suggest that consistent strenuous activity over decades may increase one’s risk of developing ALS.
When Gonzalez and her colleagues studied 51 ALS patients and 40 people with other neurologic diseases, matched by age and gender, they found that those with ALS had expended significantly more energy in their daily lives over the course of three decades, starting at age 20.
Gonzalez said it appears that regular and intense daily activity is a more common way of life for people who develop ALS than for those who don’t. She hypothesized that decades of heavy work or other strenuous exercise could create a deficit of blood flow or oxygen in relation to nerve cells’ demands. Gonzalez emphasized that a final analysis will include many more people with and without ALS.
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Nose may provide window to brain
There was general agreement at the meeting about the need for more convenient and precise ways to measure ALS progression and response to treatment.
Jeffrey Rothstein, an MDA research grantee and director of the MDA/ALS Center at Johns Hopkins University in Baltimore, reported on a new technique involving biopsies of nasal tissue that may provide better information about how nerve cells respond to experimental treatments.
Rothstein found cells that he believes are the same as nervous-system astrocytes in the nasal lining and says the new technique might be useful in testing drugs that modify astrocyte activity.
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Portable device might make trials easier for participants
Edward Kasarskis, professor of neurology at the University of Kentucky in Lexington, presented his group’s study on the use of a lightweight, portable device called an accelerometer that provides quantitative information about muscle movements.
Thirty-four people with ALS and 10 without strapped Actical accelerometers to each limb and went about their daily activities. Data from the devices were compared with muscle-mass measurements, manual muscle-testing measures and self-ratings of movements.
Investigators concluded the accelerometers have the potential to be used for outcome measures in trials and could minimize participants’ travel and reduce dropout rates.
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Multiple serious head injuries may increase risk of ALS
Incurring multiple head injuries severe enough to require medical attention could be an ALS risk factor, suggests a study by the National Institute of Environmental Health Sciences (NIEHS) of the U.S. National Institutes of Health (NIH).
The study supports observations from other studies, including one that found an elevated incidence of ALS in Italian soccer players. However, the authors interpreted their results cautiously, due to the small study size.
NIEHS scientist Honglei Chen and colleagues, who published their findings Oct. 1 in the American Journal of Epidemiology, compared 109 people with ALS in the New England area with 255 people without ALS, matching the study participants with respect to age, gender and region of New England.
Those who had sustained more than one severe head injury, with the last one occurring within the previous 10 years, developed ALS 11 times more often than those who had never sustained a severe head injury.
People who had sustained just one head injury developed ALS at about the same rate as those who had never had a head injury. Injuries to other body parts weren’t correlated with ALS.
It’s unclear how head injury could lead to ALS, but investigators offered several possibilities, including: inflammation of the injured area; disruption of the normal barrier between the circulatory system and brain (the blood-brain barrier); and damage to the energy-producing centers inside cells (mitochondria).
They say studies with larger numbers should be undertaken, with more detailed information about each episode of head injury.
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