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November 29, 2006

Major Effort Underway to Find
New Genes for Typical ALS

[Quick Summary: The ALS Association reports progress in finding gene links to ALS in partnership with The Packard Center at Johns Hopkins and the National Institutes of Health.]

A search for genes that underlie most instances of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease) has compiled genetic information on more than 1,000 patients and controls as the first step in uncovering what genetic factors might play into the disorder.

Researchers in the study, supported by The ALS Association, The Packard Center for ALS Research at Johns Hopkins, and the National Institutes of Health present their initial findings this week at the 17th International Symposium on ALS/MND at Yokohama, Japan.

Bryan Traynor, M.D., together with John Hardy, Ph.D., both with the National Institutes of Health (NIH) are leading a team of American and Italian researchers in the million-dollar study. “If all goes well,” Traynor says, “the work will clarify the role of genes—or lack of it—in sporadic ALS (sALS). That role has long been uncertain.” He adds, “We don’t know, for example, if sALS is triggered by a handful of interacting genes or genes plus environment or environment alone.   Our study aims to clarify that.”

“This effort should make a real difference for sporadic ALS and is the kind of project that the patient DNA repository was put in place to serve,” said Lucie Bruijn, Ph.D., science director and vice president of The ALS Association.

Progress follows the successful and continuing collection samples of ALS patient DNA to fill the repository established through the National Institutes of Neurological Disorders and Stroke (NINDS). ALS patients and caregivers can donate anonymously a small amount of blood and give clinical history to aid in the gene hunt. Donations continue to be accepted at many ALS centers around the U.S. including centers certified by The ALS Association to aid in this and other projects that will uncover the reasons for the disease.

The researchers have scanned the donated DNA from patients and healthy controls for specific patterns that appear more frequently in those with the disease than those without disease. The researchers will then try to see if any differences in patterns in the DNA can be tied to changes in specific genes.

The process is called high resolution, genome-wide association mapping. It uses robotics and just-available gene finder chips. With a high-throughput process, investigators automatically mine each patient’s DNA for information with speed and accuracy not possible even six months ago. The project, which began this past summer, was completed in record time, reflecting the highly collaborative nature of the involved scientists and clinicians. The researchers anticipate important analysis in the next few months to confirm any changes in patterns of gene expression with ALS.

ALS is inevitably fatal and has evaded disease-changing treatment despite numerous research advances. The fundamental reason why nerve cells that supply muscles die in the disease remains a mystery. It has been a challenge to come up with an effective, targeted therapy.

Finding any genes whose expression contributes to the disorder will undoubtedly provide new targets for therapeutic candidates. In the decade since discovery of a mutation in the protein, copper-zinc superoxide dismutase (SOD1), the cause of some inherited forms of ALS, several more mutations relating to the disorder have been brought to light.

The genetic underpinnings of sporadic ALS, the disease that for 90 percent of ALS patients appears to arise spontaneously without family history, remain even more unclear. Even though inherited ALS is clinically indistinguishable from ALS that does not run in families, the same genes may not be responsible for both. But something is held in common in the way that motor neurons end up dying in both types of ALS. That is why a gene change identified in one type can help understand the other.

A scientifically significant tie between a gene or genes in the disease would set the stage for even larger international collaborations. To facilitate this, the raw genotype data will be made publicly available so that other ALS researchers can compare their results with the outcome of the current study.

To understand more about the genetics of ALS click here.