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July 5, 1999

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New Drug With Unusual Promise Enters ALS Pipeline

A natural compound found to be extraordinarily potent in protecting nerves from harm in a lab model of amyotrophic lateral sclerosis (ALS) will likely usher in a new drug "cocktail" approach to the disease, according to Johns Hopkins scientists.

ALS, also known as Lou Gehrig's disease, brings about a slow death of motor neurons -- the nerve cells that activate muscles -- in the spinal cord. Patients become progressively weaker until muscle use is entirely lost.

In the Hopkins studies, however, pigment epithelium-derived factor, or PEDF, safeguards nerves in the animal spinal cords that serve as models, "offering nearly complete protection," according to neurologist Ralph W. Kuncl, M.D., Ph.D., who led the research team. The research report appears in this month's Journal of Neuropathology and Experimental Neurology.

"If we had this same level of protection in patients with ALS, they'd experience slight muscle weakness at most," says Kuncl. "It's early," he adds, "but because PEDF appears so potent and seems to lack toxicity, these results are unusually promising." The team next plans to test PEDF in transgenic mouse models of the disease.

In the study, researchers pinpointed PEDF for the first time in the spinal cord and skeletal muscle of humans, monkeys and rats. Prior to this, scientists thought the eyes were its prime location, in the pigmented layer of cells underlying the retina. Then, using slices of rat spinal cords kept alive in culture, the Hopkins researchers tested PEDF's ability to protect cells against the toxin THA (threo- -hydroxyaspartate), a drug that brings about slow death of motor neurons and thus mimics essential features of ALS.

PEDF-treated sections averaged near-normal neuron counts compared with untreated ones. Levels of a key enzyme typically made by healthy cells underscored the result. "PEDF may significantly protect spinal motor nerves against injury," says Kuncl. "What we have here is a potential therapy."

The results with PEDF and a compound called neurturin, reported on separately by the Hopkins group in the May issue of Molecular and Cellular Neuroscience, will likely mark a new approach to ALS, Kuncl says. Both are potent natural substances classed as neurotrophic factors, molecules which normally spark regrowth of damaged nerve cells. Neurotrophic factors may also damp down the sensitivity of healthy cells to toxic effects of the nerve transmitter glutamate, a substance that figures prominently in the disease, Kuncl adds.

In ALS, a normal "mopping up" action that clears the nerve transmitter glutamate from the spaces between motor nerve cells breaks down. A glut of glutamate and the resulting overstimulation of motor nerve cells is a hallmark of the disease. In the lab spinal cord models, adding THA also blocks glutamate cleanup, and nerve cells wither in a way indistinguishable from the real thing.

The Hopkins team has been refining their model for the past eight years, to the point, Kuncl says, where "it faithfully predicts substances known to have effects in patients with ALS." It's also a "high through-put" model, meaning the researchers can screen many potential therapies more quickly and cheaply than with traditional techniques using live animals. "We threw the kitchen sink at these spinal cord cultures," says Kuncl. "We gave them everything we thought might have some chance of working."

Legend for the image A-C. Immunostaining of 4-week-old spinal cord cultures illustrates remarkable preservation of motor neurons by PEDF. A section of an untreated control culture shows normal healthy neurons in both the dorsal and ventral horn of the spinal cord(A), but cultures exposed to 100 ÁM THA, motor neurons are especially depleted (B). Treatment of THA-intoxicated cultures with PEDF preserves neurons and their processes (C). VH = ventral horn; DH = dorsal horn.

Riluzole, the only FDA-approved ALS therapy, mildly restrains a nerve cell from releasing glutamate in the first place -- a different principle. But riluzole has "a minimal protective effect on motor neurons," Kuncl says; its effect is a small slowing of the inevitable. "PEDF and neurturin perform far better than riluzole in the spinal cord models," he adds. "With riluzole, we are at the same point chemotherapy for childhood leukemia was 35 years ago," says Kuncl. "There was one drug and it didn't work very well. But what we see coming with the neurotrophic factors is the start of an ALS cocktail -- the same approach we use for AIDS and cancer -- with a variety of drugs, each working at a different point in the process."

If PEDF proves useful in people, Kuncl adds, "it will be a classic example of scientific serendipity." The researchers on the Hopkins team discovered PEDF by chance, when a patient mentioned a researcher friend studying neurotrophic factors in the eye. More on a hunch than anything, Andrea M. Corse, M.D., also on the Hopkins team, decided to try the eye factor on the spinal cord model. "Who would have thought that a substance in eye tissues would have this effect?" Kuncl asks.

Other researchers in the project were Masako M. Bilak, Ph.D., Stephan R. Bilak, Ph.D., and Mohamed Lehar, M.D.

Funding came from an NIH grant, from the Muscular Dystrophy Association, the Cal Ripken/Lou Gehrig Fund for Neuromuscular Research, and the Jay Slotkin Fund for Neuromuscular Research.

Related Web Sites:

Research by Dr. Kuncl's team at Hopkins is on this site:

Background information on the nature, science and treatment of ALS is on this site: http://www.ninds.nih.gov/patients/Disorder/als/als.htm

For TV production: the Hopkins lab team can show the spinal cord cultures being prepared. They also can show addition of the neuroprotective drugs and the easy-to-see visual difference between protected and unprotected spinal cord sections. An ALS patient is also available to talk about the disorder.

The study is reported in the Journal of Neuropathology and Experimental Neurology, July 1, 1999, vol. 58, no 7.

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