Eighteen months ago, we persuaded Menahem Segal, PhD, a neuroscientist working at the Weizmann Institute in Israel, to attend a workshop that the A-T Children's Project sponsored in Tarrytown. New York. Although ataxia-telangiectasia is a childhood disease that includes many symptoms such as immune deficiency and a high rate of cancer, we had organized this particular meeting to focus only on the neurodegeneration of A-T. We wanted brain experts like Segal to evaluate what was already known about the neurological problems of A-T and then to generate new research plans that would help unravel the brain cell death that causes children with A-T to lose control of their muscles. FRUSTRATED BUT INTRIGUED - When the workshop ended, Segal left New York, frustrated by how little was known about the brain defects in A-T patients and in the A-T knockout mice that several labs had recently developed using genetic engineering techniques. Fortunately, although the data presented during that workshop had seemed incomplete to him, the workshop itself had introduced Segal to this disease and to the urgent need to accelerate research progress on it. It had also made him aware of how children with A-T and their families were desperately waiting for a treatment. He felt compelled to help. A-T MICE CLEARLY ABNORMAL - Returning to Israel, Segal did not forget about A-T. Instead he obtained some A-T knockout mice from another Israeli scientist, Dr. Yoram Groner, who had also attended the New York workshop. Then, together with Groner and Dr. Raya Eilam, Segal began studying the mice. First. they dipped the hindfeet of the mice in ink and then allowed them to run through a tunnel lined with paper to record their footprints. When the straightness, consistency and distance between the footprints of the A-T mice were analyzed and compared to healthy mice. Segal and his collaborators saw that A-T mice were clearly abnormal. Next, the scientists studied the levels of "open field" activity of the mice. On this measure, too, the A-T knockout mice were not normal; they were much less active. These measures confirmed that A-T mice had neurological problems. Next, Segal, Eilam and Groner examined the brains of the A-T mice under a microscope. They chose to look first at the cerebellum because it is the area of the brain that most affects motor control and in which most of` the old medical literature and autopsy studies in A-T patients indicated that there was cell death taking place. The three scientists noticed some slight anatomical abnormalities with the cerebella of the A-T mice -- such as a few Purkinje cells out of place -- but otherwise, they were disappointed that clear deterioration of the brain was not obvious. They thought that maybe the mice were still too young to show neurodegeneration, or perhaps mice were just affected differently by A-T than humans were. ANOTHER BRAIN REGION CHECKED - Segal, Eilam and Groner decided to check another area of the brain, known as the substantia nigra. Unlike the cerebellum, which looks like a separate little brain attached below the back part of the brain, the substantia nigra is located in the brain stem. Although it is a small part of the brain, the substantia nigra is quite famous in the medical world because it is the part of the brain that is known to lose cells in patients who have Parkinson's Disease -- a disease that affects over one million people in America alone. The substantia nigra has special cells that produce an important chemical or "neurotransmitter" in the brain called dopamine which, in healthy people, helps different areas of the brain communicate with each other. In Parkinson's Disease it is known that when about eighty percent of these dopamine producing cells die, many symptoms such as tremors and rigidity appear. SUBSTANTIA NIGRA IS DIFFERENT - Looking at the substantia nigra of the A-T mice, the three scientists saw evidence of missing brain cells. Next, they used an antibody that detects tyrosine hydroxylase (TH), the enzyme that controls the rate at which dopamine can be produced by cells. Using this antibody on the striatum -- the brain area that receives fibers from the substantia nigra -- they measured TH activity. If they found evidence of reduced TH activity, just as in Parkinson's Disease, that could mean that the substantia nigra tissue from the A-T mice were missing cells that produce dopamine. Sure enough, the TH staining technique showed dramatically lower levels of TH protein in the striatum of the A-T mice than in healthy, control mice. Segal, Eilam and Groner realized that the A-T mice might he deficient in their production of dopamine! Reviewing their findings, the three researchers began to wonder if the brains of the A-T mice could somehow be helped by restoring dopamine to normal levels. Because it is not possible for dopamine itself to cross the blood-brain barrier, the scientists injected the A-T mice with a drug given to Parkinson's disease patients, called "L-Dopa" (the L-isomer of 3.4-dihydroxy-phenylalanine). L-Dopa does cross the blood-brain barrier, and when it reaches the brain, the brain is able to convert it into dopamine. L-DOPA HELPS MICE - After giving the A-T mice shots of L-Dopa, Segal, Eilam and Groner once again conducted the behavioral studies on the A-T mice. To their amazement, they found that the A-T mice that had been injected with L-Dopa performed significantly better than A-T mice that had not received L-Dopa! This was the first time that any drug had been shown to help A-T mice. IMMEDIATE FOLLOW UP - This discovery set into motion a flurry of medical research activities. First, because it was critically important that at least one other lab confirm these findings, the A-T Children's Project immediately started encouraging several other labs with A-T mice to look at the substantia nigra and striatum of their animals. Already, a lab in another country has confirmed a decrease in striatal dopamine in A-T mice consistent with the Israeli group's findings. Second, we began urging several laboratories to examine the substantia nigra and striatal tissue of deceased A-T patients that has recently been collected through autopsies. This step was necessary to determine whether substantia nigra cell loss occurs in human A-T patients as it does in the A-T mice. Third, we began seeking help from certain medical centers that have state of the art imaging systems, such as "functional" MRIs and even scanning systems that can specifically monitor the activity of dopaminergic neurons in the brain. Using these brain imaging techniques would help to confirm if there is a problem with the substantia nigra in living A-T patients. NEW FINDINGS FIT WITH OLD REPORTS - Besides triggering new research activities, these new findings have prompted us to look back through medical research reports published about A-T over the last 30 years. Surprisingly, some interesting findings about the substantia nigra and dopamine in A-T patients were reported many years ago, but not much follow up was done on them. For example, a group of doctors in the USSR published an article (written in Russian) in the 1970s describing a reduction of dopamine/DOPA that they saw in 26 A-T patients. Also, in the 1980s a neuropathologist studying autopsied A-T brain tissue reported seeing abnormalities in the substansia nigra. We cannot be certain that these reports were reliable. hut they do seem to lit together with the new findings. PILOT CLINICAL TRIAL COMPLETED - Because L-Dopa is a well known, relatively low risk drug, and because the Israeli scientists clearly saw its positive effect on A-T mice, we wanted to initiate a small clinical trial with A-T patients. From the moment these new findings were announced, we started working with the A-T Clinical Center at Johns Hopkins Hospital in Baltimore to design a small clinical trial of L-Dopa. Howard Lederman, MD, PhD, co-director of the A-T Clinical Center that has evaluated over 100 A-T patients during the last two years, wrote a protocol for a double-blind, placebo-controlled, crossover trial of L-Dopa in A-T patients who are at least six years old. The FDA then approved the trial, and approval was also obtained from the Institutional Review Board at Johns Hopkins. In a two month pilot study, seven patients with A-T were given L-Dopa or a placebo (an inactive drug) under the supervision of the physicians at the Johns Hopkins Center. The drug was given in a tired dose combination with "carbidopa" to limit nausea and vomiting, the most common side effects. The families of two patients noted significant improvement; two may have had improvement but it was either very minimal or inconsistent; and three patients had no change. CLINICAL TRIAL NOW EXPANDED - Now the physicians at Hopkins have obtained approval to expand the clinical trial to many more A-T patients. They have begun recruiting additional subjects to help determine if L-Dopa will improve any of the neurological symptoms of A-T and to some but not in all A-T patients. During the help determine why L-Dopa may work in trial the active drug is given for twelve days; there is an 8-day period without any drug; and then the placebo is given for twelve days. Patients may get the active drug first or second, but all patients receive both the active and inactive forms. L-DOPA MAY NOT HELP PATIENTS AT ALL - Of course. it is very possible that L-Dopa will not help patients with A-T the way it helped the A-T mice. After all, mice and humans are different. Every researcher knows that most drugs that have worked in lab animals have not worked in humans. As mammals with physical systems somewhat like our own, mice provide a relatively quick, inexpensive way of getting at the causes of diseases and possible treatments, but they can also distort or exaggerate what we see in humans. Nevertheless. even if this clinical trial of L-Dopa does not produce any clear results in A-T patients, we are encouraged by seeing the scientific results of` basic research on cultured cells and animal models being applied in treatments of patients with A-T in a clinical setting. FURTHER STUDIES NOW FUNDED - Of course, the labs of Segal, Eilam and Groner are not sitting still. They have published their findings in a major, peer reviewed journal so that other scientists around the world can learn about their discovery. Now, they are rushing to look at other markers in the brain that can confirm dopamine-producing cell death in the A-T mice. The three investigators are guessing that besides the dopamine system. other important neurotransmitter systems in the brain. such as the serotonin and acetylcholine systems may not be functioning properly in A-T patients. The A-T Children's Project has provided research funding so that they may continue looking at how these systems are affected in A-T mice during development. Please stay tuned.