May 18, 2005
From the ALS Association

ALSA Hosts Researcher Presentation in Nation’s Capital
Roberta Friedman, PhD, ALSA Research Department Information Coordinator

Patients with amyotrophic lateral sclerosis and their families received an update on investigations into the cause and treatment of the disease, while in Washington, D.C., for the annual Advocacy Day and Public Policy Conference sponsored by The ALS Association (ALSA). Lucie Bruijn, Ph.D., ALSA science director and vice president, introduced several researchers who are working on gene therapies and on possible genetic and environmental factors behind the disease.

“We don’t know where the answers lie,” Bruijn said. “ALSA funds a diverse and flexible portfolio of investigation to capitalize on new technologies.” For instance, the ability to prevent selected genes from making protein is only a few years old, but already ALSA-funded research is bringing this RNA silencing approach to the ALS realm.

Potential Gene Therapy

Brian Kaspar, Ph.D., of Columbia Children’s Research Institute in Ohio, presented findings that are leading to a planned gene therapy clinical trial for ALS. Kaspar and his team use a harmless virus as a Trojan horse to get a therapeutic gene to the site of damage within the spinal cord. The gene produces a helping factor called IGF-1. In mice that model ALS, injecting IGF-1 gene therapy has prolonged life and preserved motor abilities.

The gene therapy is injected into muscle. Nerves that supply the muscle with nutrients take up the virus, and its gene cargo, and bring it back into the nerve cell bodies within the spinal cord as part of a normal metabolic process. The gene therapy takes advantage of this transport with the intent to provide a steady supply of the helpful factor to the neurons that are dying.

Kaspar was part of the team that showed this approach can work in the mice. He has also carried out experiments that show that exercise early in the course of the mouse’s life can add to the beneficial effect of the IGF-1 gene therapy. These mice, which are engineered to express a mutant gene that produces an inherited form of ALS, live their lives in cages and can’t usually exercise. In people with ALS, exercise may or may not be helpful. Some studies have shown athletes may be more at risk for ALS than the general population. Further research is needed to clarify the issue, Kaspar said.

The San Diego company, Ceregene, Inc., which makes the viral delivery system for IGF-1, is working with ALSA, The National Institute of Neurological Disorders and Stroke, The Robert Packard Center for ALS Research at Johns Hopkins, and Project A.L.S. to meet the Food and Drug Administration requirements to start IGF-1 gene therapy clinical trials for ALS. (see http://www.alsa.org/news/article.cfm?id=477)

New approaches that Kaspar is also pursuing include the RNA silencing strategy that stops genes from making protein. His colleagues meanwhile have started preliminary experiments to exploit the ability of the spinal cord to make new motor neurons.

Risk Factors for ALS

Lorene Nelson, Ph.D., an epidemiologist at Stanford University, explained how she and colleagues look at patterns of disease in the community and attempt to find the factors that may initiate the disease process. For ALS, only ten percent of cases can be explained by a known, single gene. A greater number of genes likely play a role in sporadic ALS, with no one gene alone sufficient to produce the disease. Exposure to environmental factors during a lifetime almost certainly influences the risk for developing sporadic ALS, Nelson said.

Some of these factors that researchers have linked with ALS include lead, mercury and pesticides. A consistent finding is that smoking carries a two fold increase in the risk of developing ALS. Some occupations are linked to an increased incidence of ALS, including electrical work and athletics. It is possible, Nelson said, that exposure to toxins in these professions might be responsible for the risk.

Clusters of ALS cases have appeared in certain groups of people, which suggest that something in the environment might be responsible. For instance, veterans who had been deployed to the first Persian Gulf War have twice the risk for developing ALS as the general population. Another study of veterans showed an increase in deaths from ALS during several wars in the 20th century.

Increased risk was also documented for the Chamorro people of the island of Guam in the Pacific. Their increased incidence of a type of ALS reached a peak in the 1950s, but has now come back to the rate for the general world population.

The rarity of ALS makes it extremely difficult for epidemiologists to carry out definitive studies, said Nelson. To aid such efforts, ALSA has helped to implement a registry of veterans through the Veterans Administration and is funding a multidisciplinary consortium of epidemiologists and other experts. ALSA has played a critical role to stimulate these cooperative efforts, Nelson noted, to rapidly create progress in areas not usually funded by the National Institutes of Health (NIH).

Search for ALS Genes

Bryan Traynor, M.D., who will be working in population genetics at the NIH, presented strategies for finding new genes associated with ALS. A native of Ireland, Traynor explained the rationale for using Irish cases of ALS as a starting point. A small country with a relatively homogenous population, Ireland presents researchers with the chance to find a founder effect, namely, a common ancestor who might have introduced a gene that is increasing the risk of the disease. A relatively high incidence of ALS is documented for people living in the northwest corner of the island, a place where the indigenous population tended to concentrate after successive waves of invaders.

The Irish registry, and similar efforts in other European countries, will provide unprecedented resources, Traynor said, to help focus the search for genes that could have a role in the disease.

TREAT ALS Initiative

Traynor also summarized the approach to prioritize existing compounds that might be helpful in ALS, for entry into clinical testing. This effort is the groundwork for an expanded, intensified effort, now formalized by the launch of a new ALSA initiative. TREAT ALS, Translational Research Advancing Therapy for ALS, channels talent and expertise into a drug discovery program, which will find new drug candidates, identify existing drugs that may produce helpful effects in ALS, and will create a clinical trials process that will be in place by the time the searches yield candidates ready to test.

For the more than 600 people affected by ALS, holding up their lit candles on the steps of the Jefferson Memorial and bringing their experiences to the attention of Congress, these encouraging developments light the way towards renewed hope that effective treatment will be found for this heartbreaking disease.