Early News From First Large Search For Sporadic Als Genes
 

From: alscenter@jhmi.edu

To: The ALS Community

Date: February 20, 2007

Subject: Robert Packard Center ALS News Network


View this article online at:
http://www.alscenter.org/news/press/070220.cfm

EARLY NEWS FROM FIRST LARGE SEARCH FOR SPORADIC ALS GENES
Packard Center researcher, support, helps key study.

The largest-scale search for genes that underlie sporadic amyotrophic
lateral sclerosis (sALS), the most common form of the disease, has
crossed its first hurdle with the successful compiling of genetic
information on more than 550 patients and controls.

The data from this first phase have revealed 34 gene changes that may
possibly be linked to the risk of having sALS. Following phases will
verify that, as well as add new data from larger populations.

"This is the first major step in finding how genetics may influence the
form of ALS that affects most patients," says Jeffrey Rothstein, Packard
Center director. "It's an important starting point, not only for
understanding sALS but also for providing specific enough tools to find
therapies."

Researchers in the study, supported by The Packard Center for ALS
Research at Johns Hopkins, the National Institute of Neurological
Disorders and Stroke (NINDS) and the ALS Association published their
initial results online this week in the journal, Lancet Neurology.

In keeping with their desire for worldwide collaboration in the next
phases of this gene search, the scientists have made study data freely
available through the Coriell Cell Repositories web site. (The
Repository is a largely NIH-sponsored bank of patient DNA and cell
cultures.)

Packard Center grantee Bryan Traynor and John Hardy, both with the NIH,
led an American team of researchers in this first phase of the
million-dollar project. Data from an equally-large Italian arm of the
study will be added later. "If all goes well," Traynor says, "the work
will clarify the role of genes that's long been uncertain. We don't
know, for example, if sALS is triggered by a handful of interacting
genes or genes plus environment or environment alone."

In the study, DNA was collected from patients and healthy controls and
successfully scanned in signpost regions called single nucleotide
polymorphisms, or SNPs. The idea was to find if specific, distinctively
patterned SNPs appear more frequently in those with the disease than
those without it.

The 34 distinctive SNPs that came out of the study so far "represent
only the tip of the iceberg," says Traynor. "Thousands of others that
are less significantly associated with ALS may ultimately turn out to be
just as important."

Critical to the work-known as a high resolution, genome-wide
association study-is its technology. It's a high-throughput approach
(that is, it treats many samples simultaneously) that uses robotics and
just-available gene finder chips to mine each patient's DNA for
information with a speed and accuracy not possible 12 months ago.

This first phase, which began last spring, was completed in record
time, reflecting the highly collaborative nature of the involved
scientists and clinicians. The NINDS, for example, contributed the
American samples in the study from among those that ALS clinicians at
multiple medical centers nationwide sent to the Coriell repositories.

In the decade since discovering the cause of some inherited forms of
ALS-namely, a mutation producing a flawed version of the enzyme
superoxide dismutase (SOD1)-a handful of other ALS-related mutations
have been brought to light.

The genetic underpinnings of sporadic ALS, however, are far less
certain. Sporadic ALS, affecting 90 percent of ALS patients, apparently
arises spontaneously without family history. Even though the disease is
clinically indistinguishable from the ALS that runs in families,
different genes may be responsible for each. Something is held in
common, however, in the way that they both kill motor neurons. An added
benefit to the new work, then, is that gene changes identified sALS can
help understand the heritable forms.

--------------------------------------------------------------------------------

Collection of samples of ALS patient DNA, earmarked for the repository
established through the National Institutes of Neurological Disorders
and Stroke (NINDS), is ongoing. ALS patients and caregivers can
anonymously donate a small amount of blood and give clinical history to
aid in the gene hunt. Donations continue to be accepted at Johns Hopkins
and ALS centers at other major medical institutions, to aid in this and
other projects that will uncover the reasons for the disease.

To contribute a blood sample for this study,
please contact :
Cynthia Crews, Research Coordinator
(301) 451-3826 | ccrews@mail.nih.gov

or

The Johns Hopkins ALS Clinic
410-955-8511


==========================

About The Robert Packard Center for ALS Research at Johns Hopkins
www.alscenter.org

Located in Baltimore, the Robert Packard Center for ALS Research at
Johns Hopkins is a collaboration of scientists worldwide, working
aggressively to develop new treatments and a cure for amyotrophic
lateral sclerosis (ALS), also known as Lou Gehrig's disease. The Center
is the only institution of its kind dedicated solely to the disease.
Its research is meant to translate from the laboratory bench to the
clinic in record time.

Scientists and clinician members of the Packard Center are unsurpassed
at moving drugs reliably and rapidly from preclinical experiments to
human trials. They're linked, directly or indirectly, to the world's
major pharmaceutical and biotechnology companies, which have both
infrastructure and experience to make promising drugs into therapies.

Packard Center scientists are the first to propose and test a
combination approach to drug therapy, a tactic that has worked for AIDS,
cancer and other diseases.

ALS is a devastating, progressive neuromuscular disease that causes
complete paralysis and loss of function - including the ability to eat,
speak and breathe. ALS progresses quickly and is not curable. Most
patients die within five years of diagnosis.

For more information about The Robert Packard Center for ALS Research
at Johns Hopkins, including information on its latest research and
treatment, visit www.alscenter.org

==========================

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_________________________________________
Rebecca Berger
Administrative Coordinator
Robert Packard Center for ALS Research at Johns Hopkins
5801 Smith Avenue | McAuley Suite 110
Baltimore, MD 21209
410.735.7678 direct
410.735.7680 fax
rberger6@jhmi.edu
www.alscenter.org

_________________________________________
Rebecca Berger
Administrative Coordinator
Robert Packard Center for ALS Research at Johns Hopkins
5801 Smith Avenue | McAuley Suite 110
Baltimore, MD 21209
410.735.7678 direct
410.735.7680 fax
rberger6@jhmi.edu
www.alscenter.org

Genetic clues to ALS
BY JAMIE TALAN
jamie.talan@newsday.com

February 20, 2007, 8:40 PM EST

Scientists conducting an entire sweep of the human genome in patients with Lou Gehrig's disease, officially known as amyotrophic lateral sclerosis, have identified 34 possible genetic players -- although no home runs yet, according to a study in the latest issue of Lancet Neurology.

Dr. Bryan J. Traynor, a federal scientist at the National Institute of Mental Health who also works at The Johns Hopkins University School of Medicine, and his colleagues have long been interested in finding out whether there is a genetic trigger in patients with no obvious family history of the fatal motor neuron disease that claimed the famous baseball player.





Like other neurodegenerative diseases such as Alzheimer's and Parkinson's, scientists have identified a small percentage of families who pass along a disease gene. In ALS, that accounts for less than 10 percent of all patients. But Traynor and others believe that genetic abnormalities do play a role in many patients without a family history.

In an attempt to identify genes in these "sporadic" ALS patients, federal scientists at several laboratories at the National Institutes of Health and at Hopkins, in addition to the ALS Association, scanned the entire genome of 276 patients with sporadic ALS and an equal number of people with no history of neurological disease.

The latest genetic technology allows scientists to study more than 550,000 single nucleotide polymorphisms, or SNPs, genetic variations at specific points along the entire geonome. The current estimate is that the human genome comprises about 20,000 genes. In this study, they found a good, strong signal in 34 SNPs.

"This is very exciting," said Lucie Bruijn, science director and vice president of the ALS Association. "Now, scientists have to evaluate these potential genetic candidates. Some could be key players in sporadic forms of the disease."

Bruijn, whose foundation helped design and implement the study, said there is a growing repository of DNA samples from ALS patients, which can be used to study what genes are involved. Once specific genes are targeted, scientists can better understand the disease process and point the way to novel treatments.

There are no treatments that work to stop the damage of motor neurons in the disease. Patients with ALS lose their ability to move as the damage spreads and the cells lose connection to the muscles throughout the body. Patients become trapped inside their bodies, paralyzed, and, on average, die within five years.

"There is no big gene that explains this risk in sporadic patients," said John Hardy of the National Institute on Aging, who collaborated in the project. He suspects that there are many genes that can put people at risk for ALS. Just which genes they are is still not known, but this study moves scientists closer to these genetic targets.

Traynor explained that many of the genetic variants identified are involved in building the structure of the motor neurons, which have very long tails, or axons, that must extend a great length to communicate with muscles throughout the body.
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