May 11, 2005
Without question, ALS – or Lou Gehrig’s disease – is one of the most debilitating and devastating of all diseases, and NINDS takes the need for treatments in this community very seriously. As many of you already know, ALS is caused primarily by the loss of nerve cells called motor neurons. These cells reside in the brain and spinal cord, and relay control signals from the brain to muscles throughout the body – including those of the limbs, face and respiratory system. Although the clinical presentation varies widely, the death of motor neurons in ALS eventually leads to increasing difficulties with movement. These often occur first in the hands or feet, but occasionally begin in muscles such as those that control the tongue and swallowing. Regardless of the site of onset, the disease is relentless, and it gradually robs affected individuals of all motor function over a period of months or years. Approximately 5,000 people in the United States are diagnosed with ALS each year, and only 10 percent survive beyond five years after the onset of symptoms. Despite the advances made in ALS research and continued improvements in supportive therapy, current options for disease-modifying treatment are quite limited. Only one drug – Riluzole®, an inhibitor of the excitatory neurochemical glutamate – is approved by the U.S. Food and Drug Administration (FDA) for treating ALS, and it only extends survival by a few months.
Researchers do not fully understand what triggers motor neurons to die in people with ALS, but several factors have been implicated, including the increased cellular stress caused by the need for these neurons to maintain tremendously long connections with distant cells; overstimulation by excitatory nerve chemicals, like glutamate; and the activation of specific signals inside the cells that lead to their destruction. In 1991, researchers funded in part by NINDS published the initial discovery of a genetic link to ALS, specifically the chromosomal mapping of a gene that was believed to contribute to the hereditary form of ALS. This discovery later led to the identification of more than 100 mutations in this gene, along with the recognition that it normally codes for an enzyme called superoxide dismutase (SOD1), which helps clear damaging free radicals from cells. Only ten percent of ALS cases have been found to be associated with inherited genetic mutations, and mutations in SOD1 only a small fraction of those. In addition, researchers still do not fully understand how SOD1 mutations make people more susceptible to developing ALS. However, the discovery of this first gene energized investigators by providing the scientific community with new insights into possible mechanisms of disease, and by offering a means to create useful animal models of ALS that could be used for studying disease causality and testing treatments.
To adequately address all of the issues that impact the ALS community, NINDS supports a continuum of research: clinical research to rapidly test available therapies; translational research to move basic science towards clinical applications; and basic science research to expand our understanding of the causes of ALS.
Several ALS clinical trials are actively recruiting subjects, including a NINDS-funded Phase III trial of insulin-like growth factor-1 for ALS, for which enrollment is nearly complete. This trial takes advantage of the potential for a naturally occurring protein that promotes nerve cell growth and survival to delay loss of muscle strength, improve function, and extend survival in people with the disease. Enrollment is also underway for a Phase III trial of the antibiotic minocycline for treating ALS. In addition to its antibiotic properties, minocycline can also suppress cell death signals and inflammation – and has shown promise in delaying disease progression in several animal models of neurodegenerative disease, including ALS. The data from preclinical work in animals, in combination with safety and tolerability information provided in a Phase I/II human study of minocycline, provided support for its advancement into Phase III testing.
In addition to these ongoing studies, the Institute is also supporting several new translational research programs and clinical studies that herald a new era of patient-focused research at NINDS. As a prime example of the momentum in the field, ALS researchers have recently participated in the screening of a number of drug candidates with possible effectiveness in treating the disease. NINDS conceived of this novel program for academic researchers, and designed it to enable rapid screening of potential therapeutic compounds with known bioactivity and/or safety in humans, so that the most viable candidates could be quickly moved forward into clinical trials. Initiated in 2001 in collaboration with the Amyotrophic Lateral Sclerosis Association (ALSA) and two other private funding organizations, the program supported the screening of more than a thousand bioactive compounds in nearly 30 laboratory models of nerve cell degeneration. Over 75 percent of these drugs were already FDA-approved, which means that researchers could also access some information on the toxicity of these compounds in humans. The availability of toxicity information is a significant advantage for the research community, since it can save years of time in the drug development process for any agents that are moved forward into subsequent testing. In the models that were most relevant to ALS, a group of antibiotics related to the penicillins emerged as the candidates with the most potential for further study. These antibiotics are not only effective in killing bacteria; they were also found to protect cells from the toxicity of mutant SOD1 and to activate a gene for a glutamate transporter – a protein found on the surface of glial cells (non-neuronal cells that provide support and nutrition to nerve cells) that helps remove excess glutamate from the spaces surrounding nerve cell connections. Too much glutamate in these spaces can stress cells via overexcitation; and this process may occur in people with hereditary ALS as well as the sporadic form of the disease. After identifying this family of compounds in the large drug screen, researchers moved quickly to evaluate the most promising member of this family – ceftriaxone – in additional laboratory tests and preclinical studies of neuroprotection. Recent results indicate that ceftriaxone can stimulate the glutamate transporter gene in intact animals, and can protect neurons both in animal models of oxygen deprivation injury and ALS. Moreover, NINDS, in partnership with ALSA and Project ALS, contracted a study that demonstrated that ceftriaxone can delay the loss of muscle strength and death in an animal model of ALS as well.
With these results in hand, clinical investigators designed an integrated clinical trial to explore the safety, tolerability, and ultimately the efficacy of ceftriaxone in people with ALS. Typically, NINDS relies on investigator-initiated research proposals to attain most of the Institute’s clinical research goals. In most cases, these investigators conduct Phase I and Phase II studies to explore dosing, safety, and tolerability, then analyze the results before submitting a separate application for a Phase III trial to explore the efficacy of a particular therapy. In the ceftriaxone trial, NINDS worked with the applicant to use a design feature that is new to ALS and neurology, but not to the field of clinical research, that allowed the separate trial phases to be combined into one integrated study. In the three-step ceftriaxone trial, investigators will first determine the optimal dosage of ceftriaxone in a small group of 60 subjects, and will continue in a second step to examine the safety and tolerability of the drug in these same individuals. If sufficient levels of the drug are well tolerated in these participants, the researchers will expand the trial to 600 participants, in order to determine if the drug prolongs survival. The advantages of this approach are that it can eliminate the 9-22 months that are often required for the review of a Phase III trial application, and the study can still be stopped early if the equivalent of the Phase II results are negative or discouraging. NINDS has recently initiated funding for this trial and expects to begin recruitment in the fall; the Institute hopes this trial will serve as a first step in the successful translation of this therapy into clinical practice.
Many researchers exploring potential treatments for neurodegenerative diseases have also considered the antioxidant and health supplement coenzyme Q10 (CoQ10) as a promising candidate. Its ability to penetrate the nervous system and protect cells from oxidative stress, combined with its excellent safety profile, has stimulated interest in the drug for the treatment of Parkinson’s disease, Huntington’s disease, and ALS. In April 2005, enrollment began for a Phase II trial supported by NINDS that is designed to examine the potential of high-dose CoQ10 to treat ALS. Like the ceftriaxone study, this trial will also be conducted in several sequential steps. In the first part of the trial, investigators will identify the optimal dose of the drug; in the second, they will collect preliminary evidence of efficacy using a number of different outcomes, including functions needed for daily living, and measures of lung capacity, fatigue, and quality of life. Although a conclusive determination of efficacy may not be available at the end of this study, NINDS hopes that it will facilitate the collection of data needed to plan a phase III trial.
Although the need for therapies designed to intervene in the cellular events that cause ALS is essential, NINDS also supports strategies to prolong survival by improving the clinical care of ALS patients. Specifically, the clinical literature suggests that respiratory and nutritional support can independently improve survival in people with ALS. However, issues such as the identification of the optimal timing for initiating respiratory support; the best method for improving the tolerability of appliances that facilitate respiration; and the development of better techniques to assess the balance of energy consumption and use have not been addressed in well-designed clinical studies. NINDS has recently funded a Phase II trial to collect data on these and other issues; this information will enable investigators to design a Phase III trial of combined respiratory and nutritional therapy. This trial is slated to begin enrollment in the very near future, and NINDS is enthusiastic about the possibility that these two approaches might have synergistic effects in treating ALS, and may in the future be combined with therapies that target the cellular mechanisms of the disease.
As a complement to the translational grants program, NINDS has also established a facility at the Southern Research Institute in Birmingham, Alabama, that is miniaturizing laboratory tests relevant to neurodegeneration; automating them via robotic technology; and then using them to rapidly screen a collection of approximately 100,000 chemically diverse, non-proprietary compounds. By enabling the academic research community to have access to the type of drug screening resource that is normally only available to the pharmaceutical industry, the Institute is hoping to accelerate the identification of potentially useful therapeutics for a number of neurodegenerative diseases, including ALS. To date, two “test-tube” models of ALS are already being used at the facility to screen for drugs that may be useful in treating ALS, and researchers at the facility have already identified several drugs as possible “hits” in these screens.
In addition to these specific programs, NINDS-funded researchers continue to independently explore potential therapies for ALS that target a wide range of cellular processes. As suggested above, inflammation is one potential contributor to ALS that is gaining attention among translational and clinical investigators. Along these lines, recent data have suggested that a novel anti-inflammatory compound called pioglitazone can improve motor performance, delay the death of motor neurons, and extend survival in a mouse model of ALS. Further work will be required to confirm these effects in animals, but the continued success of these researchers in identifying novel therapeutic compounds is encouraging.
Basic Science Research
Mitochondria, the energy generators of the cell, are also emerging as a target of enhanced interest among ALS researchers, including those studying how mutations in the SOD1 gene cause motor neurons to be uniquely vulnerable in ALS. In 2004, two independent groups of researchers discovered important clues that suggest a prominent role for these cellular structures in the death of motor neurons. In one study, investigators explored the effects of SOD1 mutations on mitochondria, and found that the vulnerability of motor neurons in ALS may be linked to an unexpected buildup of mutant SOD1 proteins inside the mitochondria of the spinal cord, where they can cause the subsequent degeneration of affected neurons. In a second study, a separate group of researchers explored the function of the mutant SOD1 protein and found that within spinal mitochondria, these proteins may bind to and specifically trap other proteins that are necessary for cells to survive. By taking the cell survival proteins out of circulation, the mutant SOD1 proteins may be contributing to the neuron’s ultimate demise.
NINDS-funded investigators also continue to study the genetics of ALS – specifically the genetic changes that lead to inherited forms of disease. In addition to the mutations in SOD1 that cause an adult-onset form of ALS (ALS1), researchers also discovered in 2001 that a mutation in a different chromosome can cause a rare juvenile-onset form of ALS (ALS2). Then, in 2004, investigators found a link between a second form of childhood-onset ALS (ALS4) – one with a clinical syndrome distinct from ALS2 – and a known gene called Senataxin that is believed to play a role in the control of protein production following the activation of specific genes. This discovery involved the analysis of genetic material from four different families in the U.S. and Europe, highlighting the importance of the contributions from affected individuals to the research process.
Although researchers now have a better understanding of the genetic contributors to ALS, the search for genes that play a role in this disease is not yet over. For many years, NINDS has recognized that genetic researchers would benefit from having access to many well-characterized DNA samples from people with specific neurological conditions. To address this need, the Institute established a Human Genetic Resource Center at the Coriell Cell Repositories in New Jersey, in September 2002. As part of their contract, Coriell maintains a repository of data, cell lines, and DNA samples for the study of the genetic factors contributing to neurological diseases, including conditions like ALS that affect motor neurons. Genetic information is absolutely critical for the study of these conditions, as an understanding of the mutations in genes linked to ALS can help clinicians identify who is at risk for the disease, and can aid researchers in characterizing the disease process and identifying potential points of intervention. The positive effects of the repository on research in other neurological conditions are already evident, and NINDS is working with ALSA and the extramural research community to try to accelerate the rate of contributions of samples that are useful for ALS research.
As mentioned above, an understanding of the genes that play a role in the development of ALS can serve as a springboard for researchers searching for new strategies to treat the disease. The promising technique of RNA interference (RNAi) is one such strategy that is receiving a great deal of attention across many fields of medical research for its potential in treating diseases caused by known genetic mutations. Investigators both here in the U.S. and overseas have already begun to explore its applicability to inherited forms of ALS. Researchers initiate RNAi by delivering small pieces of genetic material that match those coding for an unwanted protein in a cell. By “binding up” the genetic intermediates that lead to toxic protein production, these proteins can be reduced or eliminated in the target cells. Although U.S. researchers are still in the very early stages of exploring this therapy for ALS, results from a recent study suggest that a well-designed RNAi strategy might be capable of simultaneously counteracting the more than 100 possible mutations in the SOD1 gene that can contribute to the development of hereditary forms of ALS. This proof-of-principle study is encouraging, and will hopefully lead to additional tests of this approach in animal models of the disease.
Though much of the basic science research described above is focused on improving our understanding of the causes of ALS, NINDS also supports other areas of fundamental neuroscience that may have an impact on the disease. For example, nervous system plasticity and stem cell research are particularly promising fields of study for ALS researchers, since the replacement of the motor neurons lost to the disease and the stimulation of these replacement cells to make contact with their original targets offer a reasonable therapeutic strategy.
It is widely recognized that the brain and spinal cord of adult mammals, including people, show a very limited capacity to regrow following injury. However, in recent years, researchers have shown that even the brains of adult mammals can generate new nerve cells under the right conditions. As an example, investigators have recently found that the brains of adult mice can generate new corticospinal motor neurons – which control voluntary movement via long nerve fibers they extend from the brain to the spinal cord – if the normal motor neurons are destroyed in a particular way. Importantly, these new nerve cells were also able to regrow their long extensions and make distant connections with their spinal cord targets. These findings are encouraging, as they suggest that in some cases, the body may be able to produce its own replacement cells, and that these cells may be able to make the contacts needed to restore lost function. Further understanding of what controls the generation of these cells and the growth of their long nerve fibers may facilitate the development and optimization of repair strategies for conditions like ALS and spinal cord injuries.
While promising, using “internal” replacement cells is only one approach to restoring the nerve cells lost in ALS. Investigators are continuing to explore other possible approaches as well, such as stimulating stem cells to produce a pool of motor neurons for nerve cell replacement therapy. Recently, one such group of researchers has found that motor neurons derived from human fetal neural stem cells can survive transplantation, make connections with target muscles, and support improvements in motor function in a rat model of motor neuron degeneration. In addition, a separate group of investigators has shown that they can successfully cause a line of federally-approved human embryonic stem cells to specialize to become motor neurons. Their step-wise procedure involved a sequential application of growth-stimulating molecules to the cells – molecules that researchers had previously identified as being important during nervous system development. Potential uses for these types of cells include additional studies on the development of motor neurons, the screening of drugs that could be useful in treating ALS, the testing of therapeutics in animal models of disease, or ultimately, the replacement of motor neurons in people with ALS.
Topics for Future Study
Recently-developed programs at NINDS, including the accelerated drug screening efforts and DNA repository, are fueling a more aggressive approach to these questions within the research community. To complement these efforts, NINDS also sponsored a workshop in January 2003 to explore the remaining gaps in our understanding of ALS and motor neuron biology, and released a Request for Applications (RFA) in August 2003, jointly with the Department of Veterans Affairs and ALSA. This solicitation encouraged studies of ALS in a broad range of research areas, including the causes of disease across broad populations, including genetic and environmental causes; the cellular interactions that contribute to the disease; the cellular and sub-cellular problems in affected tissues; novel approaches to delivery of therapies; and biomarkers for early disease detection. NINDS funded five applications that were responsive to this solicitation, and NIH’s National Institute of Environmental Health Sciences contributed funds to support two additional awards.
Mr. Chairman and Members of the Subcommittee, thank you for the opportunity to share this information with you. I will be happy to answer any questions you may have.
Last Revised: May 12, 2005