Research Roundup updates as of October 2004:
Cellular transport protein implicated
A research group led by Mayana Zatz at the Biosciences Institute of São Paulo (Brazil) University has identified a mutation in a chromosome 20 gene as a likely cause of motor neuron diseases in some families. Motor neurons are the muscle-controlling nerve cells.
The gene carries instructions for a “vesicle-trafficking” protein known as VAPB. The mutation may disrupt an intracellular “conveyor belt” system involved in transporting substances inside the cell.
Zatz and her colleagues studied seven Brazilian families, all with the same genetic mutation, but each with a different motor neuron disease. In some families, the motor neuron disease was classified as “typical” ALS, while other families had a more slowly progressive form of ALS or spinal muscular atrophy.
In every case, the disorder was inherited in an autosomal dominant pattern, meaning only one genetic mutation from one parent is needed to cause the disease.
The researchers, who published their results online Sept. 15 in the American Journal of Human Genetics, noted that the data may improve understanding of motor neuron loss in ALS and may provide new targets for therapy development.
“The observation that some patients, although carrying the same pathogenic mutation, may have a much milder course is very interesting,” Zatz said. “If we can understand what ‘protects them’ from the deleterious effect of the mutation, this may open new, important avenues for the treatment of ALS.”
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EmCell investigation shows poor results
Boston Globe reporter Gareth Cook recently traveled to Kiev, Ukraine, to investigate EmCell, which bills itself as having “the world’s largest clinical experience in embryonic stem cell transplantation for various diseases and conditions,” including ALS.
The reporter also spent more than two months with a Boston-area family that went to EmCell for treatment of their muscular dystrophy-affected son and interviewed other EmCell patients.
Although the clinic’s advertising suggests that it uses “embryonic” cells, which would be about five days old, the clinic director says it uses cells taken from aborted 2-week to 8-week-old fetuses. There’s no information available about how such cells are purified or tested, no animal experiments have been conducted, and treated patients haven’t been followed up at regular intervals, Cook said.
The Massachusetts boy experienced small improvements shortly after the treatment, but those later disappeared.
EmCell scientists haven’t published any papers in a scientific journal that’s reviewed by other scientists.
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Parkinson’s drug helps mice with ALS
A team of researchers in Germany and Israel published a report in the September issue of Neurology describing the possible benefits in ALS of a drug that’s now undergoing testing in people with Parkinson’s disease.
Albert Ludolph at the University of Ulm (Germany) and colleagues tested rasagiline alone and with riluzole, a drug approved for ALS treatment, in mice with an ALS-causing genetic flaw. They found that it prolonged survival in the mice but had somewhat confusing effects on function.
Mice that received the larger of two doses of rasagiline alone lived 29 days longer than untreated, ALS-affected mice, which was considered statistically significant. The longest survival occurred with a combination of riluzole and the higher dose of rasagiline — an average of 41 days longer than untreated mice.
Effects on motor (movement) function were more complicated. Early in the disease, mice treated with both drugs made less use of their running wheels than did untreated mice. Later, only the group treated with high-dose rasagiline remained more active than the untreated group.
Rasagiline and riluzole work via different mechanisms. Riluzole is thought to reduce the release of the potentially toxic chemical glutamate in the nervous system, while rasagiline may reduce a type of cellular damage called oxidative stress and may have a protective effect on mitochondria, the cells’ energy-producing units.
For up-to-date information on clinical trials in ALS, visit www.clinicaltrials.gov.
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VEGF protein helps ALS-affected mice
The naturally occurring cellular compound known as vascular endothelial growth factor, or VEGF, has been shown to play a direct role in nerve-cell survival, as well as to affect the growth and development of blood vessels.
Belgian researchers announced in May that, when VEGF genes were injected into the muscles of mice with an ALS-causing genetic mutation, they bolstered the number of surviving nerve cells, delayed the onset of ALS symptoms and extended life span.
Now, a Swedish research group led by Jan-Inge Henter at Karolinska Hospital in Stockholm, has improved motor performance and survival in ALS-affected mice by injecting the VEGF protein into the abdominal cavity. The report was announced in the October issue of Annals of Neurology.
Delivering a protein as a medication is generally more practical than delivering a gene, and approval from regulatory agencies is easier if genes aren’t involved.
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Avanir still seeks volunteers for Neurodex study
Adults with ALS and an accompanying diagnosis of pseudobulbar affect are needed for a study of AVP-923, also called Neurodex.
Pseudobulbar affect is thought to occur in ALS because of an interruption of signals from the upper part of the brain to the lower (bulbar) part. In this phenomenon a person experiences emotional expressions, such as laughing or crying, that don’t match his or her actual emotional state.
INC Research of Raleigh, N.C., is overseeing the trial. For more information, contact INC Research at (888) 255-5300.
Avanir Pharmaceuticals, makers of Neurodex, announced positive results for the drug in controlling pseudobulbar affect in ALS in 2002. The formal findings were published in the Oct. 26 issue of Neurology.
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