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| Research Update - from ALSA's National Office
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ALSA Awards Research Funds for New Investigations into the Cause and
Treatment of ALS
Roberta Friedman, PhD, ALSA Research Department Information Coordinator
The spring 2005 round of applications for ALSA now approved for a total of
$1,669,984 in funding, includes a promise of new insight into the basic
mechanisms underlying the death of motor neurons in ALS, and an invigorated
search for new genes involved in the disease, and for therapies. New to ALSA
are researchers of outstanding stature in their fields, who are turning
their focus to ALS.
Following are snapshots of the grant proposals that are awarded ALSA
funding, which comprise three starter grants totaling $119,984, and nine
multiyear grants totaling $1,390,000. Also included is ALSA-initiated
funding for an ongoing clinical trial of a candidate drug to treat ALS.
Two young investigators have received The Milton Safenowitz Post-Doctoral
Fellowship for ALS Research comprising $160,000 total funding.
Stem Cell Basics for ALS
Paola Arlotta, Ph.D., Massachusetts General Hospital and Harvard Medical
School, seeks to manipulate the specific program of gene expression that
controls how and when the brain's motor neurons form in the developing
animal. Arlotta comes from the lab of Jeffrey Macklis, M.D., that recently
published new findings on the molecular program that tells stem cells to
form motor neurons in the brain
(http://www.alsa.org/news/article.cfm?id=578.) Further details that this
newly established investigator will supply through her own collaborations
should add to the ability to implement stem cell therapy for ALS.
New Ideas about Mutant SOD1
Joseph S. Beckman, Ph.D., Oregon State university in Corvallis puts forth
the possibility that protein aggregation is actually protective in ALS
because it removes a type of SOD1 protein (the copper-containing,
zinc-deficient SOD1), which is known to be highly toxic to motor neurons. If
verified, this finding might indicate that some current approaches aimed at
preventing aggregation may be the opposite of what is needed.
Inflammation and Excitotoxic Action in ALS
Contribution of the inflammation provoking enzymes called phospholipases to
ALS remains largely unexplored, due to lack of useful inhibitors. Timothy J.
Cunningham, Ph.D., and Terry Heiman-Patterson, M.D., Drexel University,
Philadelphia, PA, have discovered CHEC-9 as an inhibitor; it suppresses
inflammation around a brain injury and rescues neurons that would usually
die. Now the researchers wish to see if it has the same effect on neurons
that are damaged in the mouse ALS model.
Another grant awarded focuses on the consequences of glutamate action.
Glutamate normally and safely allows minute amounts of calcium into neurons.
Yet excess internal calcium can trigger cell death, and motor neurons are
particularly sensitive. Malfunctioning of a cellular process that restricts
calcium entry due to glutamate was first described by Peter H. Seeburg,
Max-Planck Institute, Heidelberg, Germany. An internationally recognized
glutamate expert, Seeburg now proposes to bring his insight to the ALS field
to test the involvement of this basic cellular process in ALS.
Growth Factors and Gene Therapies
Gene therapy experiments demonstrate that VEGF has therapeutic potential in
ALS. Achieving the best route of delivery and the optimal dose depends on
the detailed knowledge of how this trophic factor works. Peter Carmeliet,
University of Leuven, Belgium who discovered important aspects of VEGF's
link to ALS, will work with Lieve Moons to find out exactly what action of
VEGF might be aiding survival in SOD1 mutant mice.
RNA interference (RNAi), specifically prevents production of targeted
proteins and can lower levels of the mutant SOD1 protein in mice. The RNAi
treatment also significantly improved hind limb motor function in ALS mice.
Patrick Aebischer, M.D., and Cédric Raoul, Ph.D., Ecole Polytechnique
Fédérale de Lausanne, Switzerland, were the first to publish this success of
RNAi in a mouse model of ALS http://www.alsa.org/news/article.cfm?id=612,
and now propose to further develop and optimize this therapeutic scheme.
New Gene Candidates in ALS:
Without a doubt, the successful hunt for new genes involved in ALS will
produce new therapeutic avenues. Following are proposed projects that will
add to the genetic information researchers will bring to bear in the design
of new treatments.
Flies have a version of alsin, the protein coded by the ALS2 gene which is
mutated in juvenile-onset amyotrophic lateral sclerosis. No one knows
exactly how defective alsin results in motor neuron degeneration. Brian D.
McCabe, Columbia University, New York, NY, will use the alsin mutant fly as
a foundation to discover genes that might be interacting with the alsin
gene, to clarify the function of this protein.
Erika L. F. Holzbaur, Ph.D., university of Pennsylvania, Philadelphia,
proposes biochemical, cellular and animal studies to see if recently
identified mutations in a motor transport protein are sufficient to cause
ALS. Her team will look at movement of cellular materials along the axons,
and at the structure of the scaffolding proteins that maintain the axons.
Andreas Kottmann, Columbia Genome Center, has discovered mutations which are
responsible for a disease called the Wolfram Syndrome, and suspects that
carriers of the mutated gene might be at increased risk to develop ALS. He
hopes to demonstrate a normally protective function of the normal gene in
experimental models of ALS.
ALS spares certain neurons while destroying most others. Eva Hedlund, Ph.D.,
and Ole Isacson, Dr Med Sci, McLean Hospital, Belmont, MA, will seek genes
that may differ in these neurons and explain their different sensitivity to
the disease.
Ammar Al-Chalabi's team, Institute of Psychiatry, London, used cutting-edge
techniques to perform the first and largest study examining genetic
variation throughout the human genome in ALS without bias. They now have a
short list of the most likely causal genes, which will be further studied in
detail.
An ongoing clinical trial is testing the ability of an anti-oxidant
compound, to prolong survival in ALS. R(+) Pramipexole is a compound that
protects neurons from the toxic action of free radicals, molecules that
react with and damage the proteins and other components of cells. The body
normally removes free radicals but in ALS there appears to be a problem with
this defense. James P. Bennett Jr., M.D., Ph.D., at the university of
Virginia, Charlottesville, will continue to investigate, under an FDA
approved trial, if the drug can slow progression of the disease.
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