Commentary: Johns Hopkins research center quickens pace in battle vs.

Amyotrophic Lateral Sclerosis, or ALS, also known as Lou Gehrig's Disease, involves the selective death of motor neurons whose job it is to enable movement of the body, including breathing. The cause of ALS is unknown and there is, as yet, no effective therapy.

ALS is usually fatal within two to five years from the time symptoms first appear. Even though the disease affects the motor neurons and movement, it has no effect on the brain itself. This allows its victims to be alert and to witness their own body's fatal downhill progression. About 5,000 new cases are diagnosed each year.

A unique approach to the study of this most frustrating disorder was established in 2000 with the dedication of the Robert Packard Center for ALS at Johns Hopkins.

Most medical research is hampered by procedures that effectively slow down the development of new therapies. Grants for research based on mere hunches or on innovative approaches are very difficult and time-consuming to obtain from usually conservative government boards. In addition, new findings normally take months before their publication, which would make them available to other researchers. The Robert Packard Center aims to streamline the research process by accelerating both the funding and the dissemination of promising findings to the research community.

The team of geniuses at Hopkins searched for and found startup funds to create a board that itself could quickly issue grants to waiting researchers in order to hasten a therapy and cure for ALS. Each year the center's scientific advisory board selects new and promising research ideas, and closely evaluates progress being made on already existing work.

Once a project is approved, the center acts quickly to extend grant money, but with certain oversight restrictions. All participating scientists must be willing to share their ideas with the team before publishing. They must also attend monthly meetings where they can gain insight into and evaluate each other's work. Finally, they must report their total progress at an annual meeting.

Does it work? You bet it does. The center's scientists are chipping away at the biology of ALS, and making progress in pointing the way to possible therapies with unusual speed. While effective therapy is the ultimate goal, the center does not neglect basic science studies that may contribute to the understanding of the biology and cause of ALS.

By constantly evaluating the ongoing research, the center makes sure it stays focused on its therapeutic target. By guiding this creative atmosphere, the center's director, Jeffrey Rothstein, M.D., Ph.D., has led the Robert Packard Center at JHU to world class recognition in the study of ALS.

At 49, Rothstein is already a full professor of neurology and has been involved in the study of ALS for over 25 years. He discovered, as a young JHU resident physician, that ALS patients had elevated levels of glutamate in the brain and spinal fluid. He speculated that something went awry that allowed glutamate to reach such high levels and thus harm nerve cells. Further study revealed that there were fewer protein-transporting molecules that usually carry glutamate away, thus allowing for the accumulation of glutamate, which contributed to ALS' destructive ways.

Rothstein then looked for and found a drug that clamped down on glutamate. Today this drug is marketed as Riluzole, the only FDA- approved drug specifically for ALS. Even though it contributes to the quality of life of the ALS patient, the drug's effects are only moderate. Nevertheless, it represents an early start toward a cure.

Promising research

Among the projects that are being advanced by the Packard Center is a collaborative study with NIH to test more than 1,000 FDA drugs and supplements that might have some effect on motor neuron diseases. A micro-assay of those revealed more than a dozen that had an effect on the motor neurons, and thus were worthy of further study.

A three-drug cocktail that significantly slowed the effects of ALS on special experimental mice was found in the Quebec laboratory at Laval University by Dr. Jean-Pierre Julien. Julien's lab also reported the likelihood of the role of the body's immune system in ALS and thus as a possible target for therapy.

Rothstein, in his own lab, is personally pursuing a novel gene therapy that is designed to extend the life of specific motor neurons that affect breathing.

Rothstein reports additional collaborative work with the Salk Institute in California. There, Dr. Fred Gage and his lab associates have reported in the journal Science (August 2003) on a method to efficiently deliver research drugs to affected mice by way of injection. The drug, known as insulin-like growth factor-1 (IGF-1), has been shown to prolong life and slow ALS progression in mouse ALS models. Rothstein cautiously commented, This is the best therapy we have ever seen in mice. He also noted that even better therapies would probably develop more rapidly as research continues.

Dr. Jonathan Glass of Emory University in Atlanta is working with de Code Genetics and other investigators at various universities around the world to isolate genes associated with sporadic ALS, its most common form.

Rothstein emphasizes that such collaboration as this among researchers and donors allow for the rapid continuation of discoveries which will ultimately lead to a cure.

You can personally contribute to this fight against ALS, while enjoying a night of fine entertainment, by attending the June 26 Tony Bennett benefit at the Meyerhoff Symphony Hall (call 410-783-8000 for details) in Baltimore.

Robert S. Coplan, M.D., M.P.H., has spent a half century studying, practicing and writing about medicine and issues facing the health care and biotechnology industries.

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