TGen may have found Lou Gehrig's trigger

Ken Alltucker
The Arizona Republic
Nov. 30, 2006 06:19 AM
Victoria Zismann of Gilbert, a senior research associate, turns off certain gene chip fluidics stations during an experiment Wednesday at TGen headquarters in Phoenix.


Researchers at TGen believe they have narrowed the genetic riddle of Lou Gehrig's disease to 50 abnormal genes, the most common of which have never been identified by researchers before.

The Phoenix-based Translational Genomics Research Institute says the new findings from a computer scan of the human genome leave researchers a trail of bread crumbs as they piece together clues about the mysterious disease, a brain disorder that afflicts up to 30,000 Americans and typically leads to paralysis and death within three to five years.

Although researchers acknowledge much work remains, they believe they have identified differences in genes that play a critical role in the neurological disease.


A healthy person has genes with a molecular stickiness that attach motor neurons to muscle. In the case of patients with amyotrophic lateral sclerosis, or ALS, research shows the nerve can repeatedly slip off the muscle and die, said Dietrich Stephan, TGen's director of neurogenomics and the study's principal investigator.

TGen's findings come from comparing DNA samples collected from more than 1,200 people with the disease to 2,000 healthy individuals.

"This will give us an opportunity to target these molecules to see if there are any drugs that interact with them in any way," said Ron Schenkenberger, the Muscular Dystrophy Association's executive vice president for research and health care services.

Stephan said TGen and other partners are plotting the next step. Money raised to fund the genetic scan has been spent, so TGen will need to raise more money to screen drugs on the biochemical pathways identified by the gene screen.


Man on a mission
Just as important as the findings, Schenkenberger added, is the speed at which researchers finished the study.

TGen and a team of more than one dozen research institutions finished the study within nine months of securing a $652,000 grant through an MDA program called Augie's Quest.

It is named after California fitness entrepreneur Augie Nieto, who was diagnosed with ALS in March 2005.

"He's made this disease his personal mission," Stephan said. He pitched the research project and matching it with TGen's genetic scanning know-how during a trip the LifeFitness Inc. founder made to TGen's downtown Phoenix campus.

"We were funded very quickly. Nine months later, we're done and presenting in Japan," Stephan said. "This was an incredibly focused, high-energy project."

The project was completed at such a quick pace in part because of the powerful computers used by TGen researchers.


Individual genetic map
The technology, known as the 500k microarray, comes from Santa Clara, Calif.-based Affymetrix. The equipment identifies genetic differences between disease-stricken and healthy patients by rapidly producing a genetic map of each individual.

"The surprising thing is the speed with which these abnormalities have been identified," Schenkenberger said. "This results from technology that was not available just a few years ago."

The findings were to be unveiled today at an ALS conference in Japan.

Several research projects contributed to the study. Donated blood came from several MDA/ALS centers, including Houston's Methodist Neurological Institute, San Francisco's California Pacific Medical Center, University of Pittsburgh, New York's Columbia University and a dozen other sites across the nation.

Schenkenberger said the MDA will consider funding another round of ALS research.

"It depends on what the needs are and what the collaboration is," he said. "We're prepared to consider virtually whatever might be required."

Schenkenberger said fitness entrepreneur Nieto is optimistic that $16 million to $19 million can be raised over the next three years to fund fast-track research such as the scan completed by TGen. His life may depend on it.



Reach the reporter at (602) 444-8285.


http://www.azcentral.com/business/ar...-tgen1130.html

From the MDA website:

http://www.als-mda.org/research/news...nome_scan.html

November 30, 2006
SCAN OF ENTIRE HUMAN GENOME
FINDS UNEXPECTED NEW CLUES ON LOU GEHRIG’S DISEASE

TUCSON, Ariz., Nov. 30, 2006 — A comprehensive scan of the human genome has identified more than 50 genetic abnormalities in people with sporadic amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), the Muscular Dystrophy Association (MDA) and the Translational Genomics Research Institute (TGEN) announced today. The most common of these abnormalities have never before been shown to play a role in the disease.

TGen researchers, announcing the findings at an international ALS conference in Japan, said the identified differences implicate genes likely to play a role in cell function that controls nerve adhesion, offering a major new avenue for ALS research. TGen researchers identified the differences by screening DNA samples from over 1,200 people with and 2,000 people without sporadic ALS using state-of-the-art microarray technology by Affymetrix of Santa Clara, Calif.

“Our findings indicate these genes produce a sort of molecular glue that attaches motor neurons to muscle. It appears that in ALS the nerve is able to peel off the muscle and, when that happens repeatedly, the nerves die,” said Dietrich Stephan, TGen director of Neurogenomics and the study’s principle investigator.

ALS is a progressive neurological disorder that leads to paralysis and death in three to five years. It has baffled researchers for nearly 140 years.

What is extraordinary about this study is how quickly this breakthrough occurred. A new fast-track research funding approach used by MDA and a new microarray technology by Affymetrix that lets researchers quickly scan people’s genomes enabled the experiment to be completed in just nine months.

“There is a revolution going on in research, and this study is a perfect example of how things are changing,” said Sharon Hesterlee, MDA vice president of translational research. “New technology is letting us look at the genome at a level of detail that was unthinkable just a few years ago and, as a result, costs are coming down, results are coming much faster and we’re seeing breakthroughs in diseases that have baffled researchers for decades.”

The Affymetrix 500K Arrays identified the genetic differences between the affected and unaffected groups and rapidly produced a genetic map of each individual.

“Just a couple of years ago, this experiment would not have been possible because there simply wasn’t a technology that enabled scientists to sift through the three billion molecules in the genome to find the genetic abnormalities that cause disease,” said Sean George, vice president Academic Business Unit at Affymetrix. “The 500K microarray used on this experiment employs the same kind of semi-conductor technology that powers super computers.”

According to MDA and TGen, the next steps center around high-throughput screening for drugs that act on the biochemical pathways identified by the DNA screen.

The massive project was funded by a $652,000 grant from MDA’s Augie’s Quest, a fast-track ALS research program, in collaboration with TGen. Blood donated for the study came from the MDA/ALS Center at Methodist Neurological Institute in Houston, the Forbes Norris MDA/ALS Center at California Pacific Medical Center in San Francisco, the MDA/ALS Center at the University of Pittsburgh, and the Eleanor and Lou Gehrig MDA/ALS Center at Columbia University in New York, as well as a dozen other collection sites throughout the United States.

About MDA
MDA (www.mda.org) is a voluntary health agency working to defeat more than 40 neuromuscular diseases through programs of worldwide research, comprehensive services and far-reaching professional and public health education. It operates 235 neuromuscular disease clinics, of which 37 are ALS-specific research and care centers, across the United States.

In 2006, MDA allocated some $7 million to ALS research and another $10 million for ALS health care services. Since its inception, the Association's expenditures for ALS research and services have exceeded $190 million.

About Augie's Quest
Fitness pioneer Augie Nieto started Augie's Quest (www.augiesquest.org) in conjunction with MDA's ALS Division. Nieto is co-founder and former president of Life Fitness, and chairman of Octane Fitness. He and his wife, Lynne, serve as co-chairpersons of MDA's ALS Division. Nieto received a diagnosis of ALS in March 2005.

About the TGen
TGen (www.tgen.org) is a nonprofit 501(c)(3) organization focused on developing earlier diagnostics and smarter treatments. Translational genomics research is a relatively new field employing innovative advances arising from the Human Genome Project and applying them to the development of diagnostics, prognostics and therapies for cancer, neurological disorders, diabetes and other complex diseases. TGen's research is based on personalized medicine. The institute plans to accomplish its goals through robust and disease-focused research.

About Affymetrix Inc.
Affymetrix Inc. (Nasdaq:AFFX) scientists invented the world’s first high-density microarray in 1989 and began selling the first commercial microarray in 1994. The microarray technology is used by the world’s top pharmaceutical, diagnostic and biotechnology companies, as well as leading academic, government and nonprofit research institutes. More information about Affymetrix can be found at www.affymetrix.com.
ADDITIONAL CONTACTS:

TGen Affymetrix Inc.
Galen P. Perry Andrew Noble
Media Relations Corporate Communications
(602) 343-8423 (408) 731-5571
(602) 377-4734 (cell) andrew_noble@affymetrix.com
gperry@tgen.org

Is this a duplication of the Packard Center research? Does anyone know how the two projects relate? Both are presenting in Japan so maybe it will become clearer there.

http://neurotalk.psychcentral.com/showthread.php?t=7539

John..
Although it looks similar...as it seems to be gene therapy /gene mapping research.. it does not look to be an exact duplication of research to me...this seems to have more advanced findings...
As in this press release it has been reported that over 50 genetic abnormalities have been identified....
My understanding is that Dr. MCCarty from ALS-TDF is over in Japan with several other members of the ALS-TDF team as we speak...so as it was revealed at that symposium ...I'm sure he will be up to speed upon his return....and will be greeted by many of us with a ton of questions...
I've learned to be guarded over the years...but this to me... looks like a very important breakthrough...not breaking out the champagne bottles just yet....but will be watching closely...and waiting patiently for Dr. MCCarty's take on this...Lisa

John and all following this story,
Sorry for double posting.But, a thread has been going fairly strongly at TDF on this subject today.Alsyoyo has just recently posted an interesting article on this. I guess we'll have to see though Dr. MCcarty's take on it when he gets back.. you and others interested in this may want to keep an eye on the link...as I don't know how frequently you guys pop in there...

http://www.als.net/forum/topic.asp?T...78&whichpage=2

Third consecutive post..but Dr.MCCarty has just responded from Japan...on the thread link above..


This work is important – it is an example of what will become more common as the newer molecular biological tools are applied to ALS – and the results from this study as well as others have been keenly anticipated by researchers ‘on the ground’. In addition to this presentation, there was a separate report at the meeting that was along the same lines from a study sponsored by the NIH. Interesting information is certainly starting to flow but it is important to keep in mind that this is just the beginning and the conclusions are probably going to shift over time. For example, in these early reports, it is not clear at all that the two separate studies were able to find the same genetic links.

Caveats: The press release from the MDA – which funded the study through Augie’s Quest funds - is much more representative of the actual study. The quote from the first line of the other press release at the top: ‘they have determined the genetic causes of Lou Gehrig’s disease’ – is certainly not an accurate statement. Splitting scientific hairs to be sure, but the top press release makes it sound as if the story is over. In contrast, this is just the beginning and furthermore, sporadic will presumably have genetic underpinnings that predispose one (in other words, increase your likelihood of getting ALS) – but not necessarily directly cause ALS. This would presumably still be an environmental insult of some sort.

I can present more details on this later when I return from the meeting.

One cannot praise too much, by the way, the hospitality and grace of the hosts of this conference.


John McCarty, PhD
Treatment Investigator,
ALS Therapy Development Foundation

Thanks for the updates, Lisa. Maybe the recent drought in ALS research results is ending.

John,
I'm hoping those genes from the NIH study..are a match for some of the ones in this research....if they are from the sounds of it we may be seeing a light in the tunnel...towards the development of effective therapies...
It will be interesting to talk to Dr. MCCarty when he comes back.. I have alot of questions lined up and I'm sure you and others will as well....Lisa

Another Packard Center press release ...along the same lines as this research....hopefully they will find similar genes in the two studies....Lisa


November 29, 2006

FIRST INTERNATIONAL GENE SCREEN FOR TYPICAL ALS IS ON TRACK
Packard Center researcher, support, helps key study.

The largest-scale search for genes that underlie sporadic amyotrophic lateral sclerosis (ALS), the most common form of the disease, has crossed its first hurdle with the successful compiling of genetic information on more than 1,000 patients and controls.

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, present their initial findings this week at the 17th International Symposium on ALS/MDA at Yokohama, Japan. The symposium is the major venue, worldwide, for reporting studies on the disease.

It’s a good beginning to the first broad screening for genes for the “spontaneous” illness which, like all ALS, destroys the motor neurons that enable movement, including breathing.

Packard Center grantees Bryan Traynor and John Hardy,
Bryan Traynor discusses the gene project at the 2006 Packard Center symposium
both with the NIH, are leading an American and Italian team of researchers in the million-dollar project. “If all goes well,” Traynor says, “the work will clarify the role of genes—or lack of it—in sporadic ALS. That role has long been uncertain,” he explains. “We don’t know, for example, if sALS is triggered by a handful of interacting genes or genes plus environment or environment alone. Our work aims to clarify that.”

In the study, DNA was collected from patients and healthy controls and successfully scanned for specific patterns that appear more frequently in those with the disease than those without it.


Researcher John Hardy
Critical to the work—known to scientists 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 six months ago.

The project, 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 its new national repository.

The researchers anticipate important analysis and conclusion-drawing will occur in the next few months.

Finding genes that lead directly to ALS or that predispose people to the disease should provide new targets for therapies. 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. That’s why a gene change identified in one type can help understand the other.

Finding a scientifically significant tie between a gene or genes and ALS in this work will set the stage for even larger international investigations. “But even if we get no associations,” says Traynor, “that would suggest that sALS isn’t gene-based, that we should focus instead on the environment.”


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

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.The researchers were funded by the National Institutes of Health, the Muscular Dystrophy Association and the Robert Packard Center for ALS Research at Johns Hopkins.

Mayo is next step in ALS research
Fri, Dec 1, 2006
E-mail this story
Related Stories• Study gives hope to Lou Gehrig's patients - Fri, Dec 1, 2006
. By Jeff Hansel

The Post-Bulletin

Scientists at the Translational Genomics Institute analyzed the genomes of 3,200 individuals to find the genetic triggers of sporadic amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease.

Next, researchers are preparing a search for drugs to treat the devastating illness. They found 50 genetic anomalies involved in development of the incurable condition.

"These genes produce a sort of molecular glue that attaches motor neurons to muscle," says a TGen statement. "It appears that in ALS the nerve is able to peel off the muscle and, when that happens repeatedly, the nerves die."

Some of the genetic abnormalities have never been linked to ALS before.

To find them, researchers analyzed blood samples from 1,200 people with the condition, and 2,000 without.

"This does not mean we've cured ALS," said Dietrich Stephan, deputy director for discovery research at the Translational Genomics Institute (TGen), the non-profit company responsible for the research. This is a necessary and important step toward a cure."

The study was conducted in TGen's Phoenix facility.

Mayo gets involved

The next phase of research, though, will take place in the Collaborative Research Building on the Mayo Clinic campus in Scottsdale.

"That's exactly where we're going to be doing the bulk of these studies," Stephan said.

Translational Drug Development, or TD2, a partnership between Mayo and TGen, will use animal models to test drugs researchers believe have potential to block the effects of ALS.

Scientists will review the genetic abnormalities to see if molecules (in other words, drugs) can be found that would block negative effects on the human body, said Ron Schenkenberger, senior vice president for research and health-care services at the Muscular Dystrophy Association.

One key, he said, is whether the potential compounds are in drugs that are already on the market -- ones approved for other uses by the Food and Drug Administration.

It is not yet known whether treatments can be quickly developed as a result of the discovery, or will instead take many years -- longer than most currently diagnosed with the illness will survive.

But the MDA, which funded the research with a relatively small amount of money -- totaling $1.3 million, according to an MDA spokesman -- says there's a possibility that potential treatments could be found quickly.

That means a search through thousands of drugs already on the market. Because they've been through the FDA approval process, their side effects and risks are already known. That means if an existing drug is found that blocks the effects of ALS, it could be used almost immediately.

Failing that, developing a new drug could take years.

Hanging in the balance are the lives of 30,000 or more Americans now living with the knowledge that life expectancy after diagnosis with ALS, according to the MDA, ranges from two to four years. But famed scientist Stephen Hawking has survived with ALS for many years, Schenkenberger said.

ALS deteriorates nerve cells in the brain and spinal cord that control voluntary muscles, according to MayoClinic.org. Eventually, people who have ALS lose the ability to move their limbs and the muscles needed to breathe.

Using new "microarray" technology by Affymetrix of Santa Clara, Calif., TGen completed the analysis -- from start to finish -- in just nine months. That, says the MDA, shows the speed of research is ramping up.

"Just a couple of years ago, this experiment would not have been possible because there simply wasn't a technology that enabled scientists to sift through the three billion molecules in the genome to find the genetic abnormalities that cause disease," noted Sean George, vice president of the Academic Business Unit at Affymetrix, in a company statement. The study used the same kind of technology that powers supercomputers, George said.

"The quicker we can identify the anomalies, the quicker we can target those for possible intervention," Schenkenberger said.

How soon?

"The time horizon is, at its best, within the lives of people who are still with us -- at its worst within the next two waves of people who are diagnosed," Stephan said.
http://news.postbulletin.com/newsman.../?a=276472&z=2