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Testimony on Amyotrophic Lateral Sclerosis, May 2000

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Statement of
Gerald D. Fischbach, M.D.
Director
National Institute of Neurological Disorders and Stroke
Before the
Senate Appropriations Subcommittee
on
Labor, Health and Human Services, Education and Related Agencies
May 18, 2000

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a devastating neurological disorder that robs people of their ability to move, eventually causing death. The progression of weakness and muscle wasting can follow several different patterns. It may begin, for example, with difficulty of fine finger movements, such as handling keys or buttons, and progress to affect muscles of the hand, arm, shoulder, and legs. Later, muscles that control swallowing and respiration become involved. Regardless of how it begins, ALS is relentless in its progression. About 5,000 people in the United States develop ALS each year, and about 90% of them die within 5 years of when symptoms are first detected.

The symptoms of ALS reflect the death of motor neurons, nerve cells in the brain and spinal cord that innervate muscles and cause them to contract, making movement possible. Motor neurons are remarkable machines. Their cell bodies, which hold the genetic blueprints and manufacture most cell components, lie in the brain and spinal cord, but each one extends a long thin fiber called an axon that projects far to connect precisely to muscle cells. Although the axons are microscopic in diameter, the total volume of a motor neuron can be 5000 times that of a typical cell because the axons are so long. The large size of motor neurons, their high energy requirements, and the extent of axons out of the protected environment of the brain and spinal cord contribute to the vulnerability of these cells.

In addition to the spinal cord motor neurons themselves, the so called "upper motor neurons" also die in ALS. These are nerve cells in the cerebral cortex that activate the motor neurons. The cerebral cortex helps coordinate the planning and initiation of voluntary movement. Upper motor neurons, like motor neurons, must support very long axons, extending as far as from the head to the lower spinal cord, and this may contribute to their vulnerability.

Although motor neurons are the best studied of all nerve cells, we don't know why cells die in ALS, why the disease selectively affects motor neurons and spares other cells, and whether a defect in the motor neurons themselves, or some other factor, triggers the disease. Most importantly, we do not yet know how to stop the progress of ALS.

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Senate Date: May 18, 2000

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How nerve cells die in ALS/What causes ALS

There are many disorders in which nerve cells die. The particular diseases that result depend on which parts of the nervous system are affected. Recent research has shown that the final steps leading to nerve cell death may be the same in many disorders including ALS, Parkinson's, Alzheimer's and Huntington's disease, and in trauma and stroke. The discovery that common themes play out in each disease offers hope because progress against one disorder will very likely help in the fight against others.

Apoptosis, or "cell suicide," is one unifying theme in neurodegeneration that has come to prominence in ALS research. Studies of the development of the nervous system, particularly in simple organisms such as nematode worms, revealed that many nerve cells take an active role in their own death. Cells invoke a step-by-step disassembly process called apoptosis. During apoptosis a cascade of enzymes takes place, in which one activates the next like the steps in a computer program, ultimately leading to the destruction of the cell. Despite the fact that apoptosis is a late step in the progression of disease, there are now tantalizing suggestions in animal models that interrupting apoptosis may slow the progress of ALS. Each step in the cascade offers targets for the development of drugs or other interventions.

In addition to the cell death cascade itself, a great deal of research is directed at insults that set it off. Cells enter apoptosis when they are damaged. Free radicals are among the leading culprits suspected of causing damage in neurodegenerative disorders including ALS. Free radicals are highly reactive chemicals that are a byproduct of normal energy metabolism. If produced in excess or insufficiently controlled, these chemicals damage critical components of nerve cells. Because nerve cells, and especially motor neurons, require so much energy to carry out their electrical and metabolic activities, they are especially vulnerable to free radical damage.

Molecular genetics is contributing greatly to our understanding of ALS, and has reinforced the suspicions about a role for free radicals in the disease process. Although only about ten percent of people with ALS inherit the disease, studying those familial cases is helping scientists to understand ALS because genetics can identify the first step in the disease,a mutant gene,in these cases. Mutations in the gene for the enzyme superoxide dismutase (SOD) cause some cases of inherited ALS. SOD normally acts to safely remove free radicals. However, it appears that the mutation may lead to ALS not because the enzyme fails to do its job, but because it creates excess free radicals. This surprising result is an excellent illustration of the power of genetics to focus attention and generate new hypotheses. Inherited ALS is clinically similar to the more common forms of the disease, and scientists are actively investigating the extent to which the underlying mechanisms of inherited and sporadic ALS are also alike. Meanwhile, geneticists are searching for other mutations that can cause this disease and provide additional clues.

The discovery of SOD mutations led to another crucial advance in ALS research. Scientists leveraged this gene finding by engineering mice that develop a disease that mimics ALS. These mice are now critical tools for studying ALS and testing treatments. Several therapeutic strategies have already shown promise in these animals. For example, the nutritional supplement creatine, a natural component of energy metabolism, extended the lives of ALS mice and is now being tested in people with ALS.

Other processes that damage nerve cells in other neurological disorders have been implicated in ALS. "Excitotoxicity" occurs when nerve cells are overstimulated by the neurotransmitter glutamate, a normal chemical signal by which nerve cells electrically activate one another. In ALS there may be a failure to clear glutamate adequately, allowing too much to accumulate. Too much glutamate can lead to abnormal accumulation of calcium within cells and this disrupts many critical cellular functions. Excitotoxicity and excess calcium can harm mitochondria, the energy factories of the cell, causing excess production of free radicals, triggering apoptosis. Free radicals can damage many parts of cells including neurofilaments, an essential component of the internal "skeleton" of nerve cells that is especially important in the long axons of motor neurons. Abnormal aggregation of proteins, including neurofilament proteins, is another recurring theme in neurodegenerative diseases that has been a focus of attention in ALS. The role of the immune system in ALS has also been a target of investigation, with some studies indicating an autoimmune attack on calcium channels in ALS. (However, a variety of immune based therapies have been tried and failed to slow the disease.) Similarly, there have recently,and in the past,been suggestions that a virus may be associated with the disease in some way, but further investigations will need to determine whether a virus can actually cause the disease. Understanding how these processes come together to cause ALS, and what triggers the harmful interactions to begin, is a complicated puzzle that must be solved to defeat ALS.

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How nerve cells live

Despite the accumulating information about what causes nerve cells to die, we still don't know why neurodegeneration begins in ALS. It is also a mystery why nerve cell death proceeds so quickly, compared with disorders like Parkinson's and Alzheimer's. The rapid progression of ALS may reflect a downward spiral of effects, each one triggering the next. In addition to processes that damage nerve cells, the disruption of factors that normally sustain cells may be critical. In other words, to understand ALS we must attend not only to how nerve cells die, but also to how nerve cells live.

Nerve cells do not live in isolation, but continually engage in conversations with other nerve cells, with supporting cells called glia that greatly outnumber nerve cells, and with target cells, such as muscles, to which motor neurons connect. Glia, for example, are largely responsible for clearing excess glutamate to prevent excitotoxicity, and a deficiency in glutamate clearance has been implicated in ALS. So, although motor neurons have been the obvious focus of research in ALS, other cells may also play a crucial role in this disease. Understanding these complex interrelationships is critical for understanding what triggers ALS and why it proceeds so rapidly.

The neuromuscular junction illustrates the intricacy of communication between cells, which includes not only rapid messages that evoke muscle contraction but also more slowly acting factors that influence cell growth, survival and specialization. The neuromuscular junction is the functional connection, or synapse, between the axons of motor neurons and muscle cells. The motor neuron axon and the muscle cell each form highly specialized, precisely aligned structures that together make up the neuromuscular junction. The result allows rapid and reliable activation of muscles by neurotransmitters released by the axon. During the development of the neuromuscular junction, the motor neuron axon and the muscle cell intimately exchange signals that guides each to form its part of the junction. Likewise, even in the adult, there is a continual remodeling of the junction with an ongoing interaction between nerve, muscle and glial cells.

Natural growth and survival molecules called neurotrophic factors are one token of the slower, nutritive communication between cells. The receptiveness of cells to these molecules depends on how electrically active cells are. So, as motor neurons are damaged, for whatever reason, their interaction with other nerve cells, glial cells, and muscle may be affected, leading to further problems. Experiments using neurotrophic factors as therapy have produced some promising results in animal models of ALS and other neurodegenerative disorders. So far, success has not followed in people with these diseases, although trials are continuing. The lack of early success is not surprising, and should not be discouraging, given how difficult it is to get neurotrophic factors into the brain and spinal cord where they are needed and how little we understand about which molecules, perhaps in combination, are most appropriate.

Other areas of fundamental neuroscience are also likely to have a bearing on ALS research in the future, and ALS has attracted the interest of some of the best scientists from many areas of research. There has been astonishing progress in understanding the steps by which a primitive embryonic cell becomes a highly specialized motor neuron. Within cells chemical messengers called transcription factors bind to specific regions of DNA and turn on and off particular genes, thereby regulating the fate of the developing cells. Which genes are active in a cell determines what kind of cell that cell will be. The transcription factors, in turn, are regulated by chemical signals from neighboring cells. Insights about how motor neurons specialize to differ from other nerve cells provide essential clues for understanding why these cells are selectively lost in ALS. Strategies, such as gene therapy, might also exploit the gene control elements to target potential therapeutic genes to motor neurons. Perhaps in the not too distant future, the developmental pathways might also be invoked to generate replacement motor neurons from stem cells.

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Developing therapies.

The more we understand what causes cells to die in ALS and what nerve cells need to live, the more rationally we can develop therapies. Drugs might plausibly target any of the processes implicated in ALS,free radical damage, excitotoxicity, calcium concentration, apoptosis, and so on,or therapeutic interventions might supplement sustaining factors like neurotrophic factors and electrical activity, try to replace or repair defective proteins such as SOD or even aim to replace lost cells. A combination of approaches may well be the best strategy.

Pharmaceutical companies use a technology called high throughput screening to accelerate the development of new drugs. Using robotics, this approach screens hundreds of thousands of chemicals in a short time to identify lead compounds for drug development. Although industry invests heavily in high throughput screening, private companies are less likely to focus on relatively uncommon disorders such as ALS. NINDS is trying to find the best ways to put this technology in the hands of researchers who are focusing on ALS and other neurological disorders. An important part of the high throughput strategy is the requirement for simple, repeatable assays, or tests, for the effectiveness of a potential drug. On April 10-11 NINDS, working closely with private ALS and SMA groups, held a workshop on "Assays for High-Throughput Screening of Drug Candidates for Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy" to help guide that effort. The meeting brought together experts from academia, large pharmaceutical companies, small biotechnology organizations, government and private advocacy groups. NIH will follow up with specific programs to foster the development of assays and to make the robotics, chemical libraries, and other requirements for high throughput drug screening technology accessible to academic investigators.

Several other new therapeutic strategies now on the horizon may also apply to ALS. NIH is very interested in the development of safe and effective stem cell and gene transfer therapies, to name two areas of medicine that have properly captured the public's attention. Stem cells are developmentally primitive cells that can be coaxed to multiply and to specialize to form particular cell types, such as motor neurons. Stem cells might ultimately provide replacements for lost cells, but these versatile cells can be used for therapy in other ways. Stem cells, perhaps altered by genetic engineering, might augment the tissue's ability to clear glutamate or provide neurotrophic factors. Gene transfer therapy likewise might be employed in several different strategies, beyond replacing defective genes, for both inherited and non-inherited forms of disease. Providing neurotrophic factors via gene transfer therapy is one strategy that has shown promise in animals for ALS and other neurological disorders. While stem cells and gene transfer therapy have great potential, each also presents difficulties that must be resolved before their application in people with ALS, and both require substantial investments to build a foundation of basic biological understanding.

Developing better means to deliver therapeutic agents,drugs, cells, and genes,to where they are needed in the brain and spinal cord is another focus of attention with implications for ALS and many other diseases. The blood-brain barrier (and blood-spinal cord barrier) normally exclude many potentially helpful drugs. Surgical access to the brain is itself not a trivial matter, even with the dramatic advances in brain imaging to guide surgeons, and better methods for physically introducing therapeutics to specific regions of the brain are needed. Likewise, the ongoing efforts to develop drugs that target free radical damage, excitotoxicity, and apoptosis may have a broad range of applications. Just as common mechanisms of damage in many neurological disorders provide synergies for progress, the shared obstacles to therapy for many diseases can also have a positive effect as insights gleaned from each may apply to others.

Although investigator initiated research proposals are at the heart of NIH strategy, we actively stimulate research in particular disorders when emerging scientific opportunities or public impact of a disease warrant such intervention. On both counts we certainly believe ALS merits special attention. The NINDS extramural program has been reorganized with creation of a Neurodegeneration Cluster that reflects the common themes driving neurodegeneration research. We are working to enhance research on ALS in a number of ways, including grant solicitations, workshops, and informal discussions with the research community, and are working closely with ALS advocacy groups in many of these efforts. In March 2000, NINDS released a request for applications (RFA NS-01-004) "Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and Other Motor Neuron Disorders." This RFA sets aside $3 million to fund novel approaches to understanding and treating ALS, spinal muscular atrophy, and other disorders whose cardinal feature is a loss of motor neurons. Given the time required for investigators to write applications and for staff to review and fund new grants, successful proposals are expected to begin in FY 2001. In March NINDS also released an RFA (RFA NS-01-003) entitled "Mitochondrial Function in Neurodegeneration." There is compelling evidence that mitochondria, the energy factories of the cell, play an important role in the generation of free radicals and in apoptosis in ALS and other neurodegenerative disorders. Several of the broad NIH efforts to provide access to emerging technologies, such as gene arrays and transgenic mice, will also be important for ALS research.

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Conclusion

The best strategy to find a cure for ALS is to support a broad research program, including research focused on ALS, on common themes in neurodegeneration, and on fundamental neuroscience, with an emphasis on funding the best quality science. It would be a disservice to patients and families to make promises about when this disease will be cured. The problems ALS presents are complex and medical progress is notoriously difficult to predict. However, most researchers, energized by progress in fundamental neuroscience, about neurodegeneration in general, and on ALS in particular, feel a cautious optimism that stopping ALS and other neurological disorders is a realistic goal. We share that belief, and will continue our efforts to speed the day when we can better treat, cure, and ultimately prevent ALS.

Last Updated: May 18, 2000.

National Institute of Neurological Disorders and Stroke
National Institutes of Health
Bethesda, MD 20892

Last updated February 09, 2005