Research takes time
A typical research project involves a hypothesis, or question to be answered, and lasts three - five years. Often, as a project is underway, new questions arise. Thus a single project often leads directly into a new project. The goals of ALS research projects are to understand the mechanisms of motor neuron death and to identify ways to keep motor neurons alive and functioning normally. Motor neurons are the cells in the brain and spinal cord which are responsible for conscious muscle contraction (i.e., function). These nerve cells are the primary target for degeneration in ALS. In order to understand what motor neurons need to function correctly they need to be studied under normal conditions, and then in situations where they are “stressed”. Examples of stress can be changes in oxidative state, changes in expression of specific genes or proteins, or exposure to varying levels of compounds which are toxic. Motor neurons can be studied just as an isolated cell population (“in the dish”), or in combination with other types of cells (also “in the dish”). To study the cells in more detail, genes (i.e., DNA) or proteins may be isolated from inside the cells and then examined using state-of-the-art technology. In some cases, the functional properties of proteins with very specific locations in the motor neurons (i.e., receptors in the membrane, or intracellular organelles responsible for generating energy) are measured using other highly sophisticated techniques.
Research costs money
One single research project costs on average $120-140,000 per year for three to five years. This cost does not include the salary support for the principal investigator (basic scientist or clinician) or for graduate students or research fellows responsible for carrying out the project.
Basic science discoveries lead to candidate ALS therapies
Whenever there is a promising lead from this type of basic science work, it needs to then be verified in studies using animal models of ALS. A number of such models exist; these primarily use mice. There are also a few rat models which are more useful for testing therapeutic interventions that require surgical approaches. Animal studies require one - two years to carry out. Positive results from such “preclinical trials” then need to be embraced by the pharmaceutical industry to be developed into therapies which are safe and can be effectively targeted to the nervous system in humans.
Important developments in the past 10 years
The past 15 years have seen an enormous growth in the number of research projects (both basic and clinical) devoted to ALS. Here we will mention just a few of the important areas which have been the focus of research during the past 10 years:
- Glial role/ inflammation | Motor neurons in the brain and spinal cord are in contact with a large number of surrounding cells. Some of these are also nerve cells, but many of them are not. Those cells, called glia, serve to provide and maintain a supportive environment for motor neurons. Recently, it was also recognized that the glial cells can undergo changes which make them aggressively harmful. That process is known as neuroinflammation. Approximately 10 years ago, anti-inflammatory drugs were tested as likely agents to slow or halt the progression of ALS. The clinical trials were not successful. Since those disappointing results, a number of labs have gone on to study the glia and the neuroinflammatory process in much greater detail, in order to identify better compounds and therapeutic delivery strategies. One new agent believed to act on this system is entering clinical trials shortly. ALS Canada funds research in the area of neuroinflammation.
Stem cells | Stem cells are undifferentiated cells which have the potential to divide and turn into a number of differentiated cell types. Legal and ethical issues surrounded the isolation and characterization of human stem cells, limiting the study and testing of such cells for therapeutic approaches. Several years ago, the possibility of using cells isolated from adult human skin (or some other tissue sources) to prepare stem cell-like populations has led to an explosion of research in this field. Studies published since the original discovery have confirmed that skin isolated from ALS patients can be used to produce stem cells which have many of the characteristics of embryonic or fetal stem cells. Further work is now underway to define and confirm the factors needed to turn such stem cells into motor neurons or into cells which might surround the motor neurons and provide support and protection to motor neurons. Currently, the first U.S. FDA-approved clinical trials for use of stem cells in ALS patients is underway. That study uses “neural stem” cells derived from an embryo. It is a study whose goal is to establish a safe protocol for introducing stem cells into the patients’ spinal cord and to determine that no measurable harmful effects result from the transplantation of such cells. Many questions remain, including do the stem cells actually survive after transplantation, what kind of cells do they turn into, will they form tumours or lead to malignant growths in the spinal cord, do they help the motor neurons to survive longer, and of course do they contribute to slowing or halting the progression of ALS. ALS Canada funds research in the area of stem cell differentiation and function.
- Diagnostic markers | One significant challenge for ALS patients is the length of time between the first appearance of functional losses (symptoms) and confirmation of the diagnosis. In addition to the psychological consequences of uncertainty for the individual and their loved ones, clinicians and scientists believe that this window of time is a missed opportunity to save a number of motor neurons which are in the process of degeneration, but not yet lost, using whatever treatment(s) are available. Diagnostic markers—either compounds which can be readily measured in blood, cerebrospinal fluid, or tissue biopsy; or non-invasive measurements of the nervous system using imaging-- are desperately needed to speed up confirmation of diagnosis. Further, markers of the disease progression are needed to provide the most rapid possible answers about the effectiveness of any treatments being tested in clinical trials. ALS Canada funds research to develop diagnostic markers for ALS.
- New genes | Approximately 10 per cent of ALS is directly inherited as a result of mutations in one of several possible genes (familial ALS, or FALS). While most ALS is not hereditary (sporadic), clinically most FALS is indistinguishable from sporadic ALS. Thus, information gained from the study of the genes which are identified in FALS should provide clues about mechanisms and intracellular pathways pertinent to sporadic ALS as well. The first gene directly causative for FALS was identified in 1993 (mutations in SOD-1); in the past 10 years five additional new genes have been identified. Genes which have already been identified in FALS cases have served as the basis for developing laboratory models (both cellular and whole animal). Most of what we have learned about mechanisms of ALS in the past 20 years has been the result of the creation and study of these models. Further, these models serve an important function in the development of therapies as they are used for “preclinical” screening of potential therapies before they can be developed for use in human clinical trials. Lastly, genetic screening can be provided to rapidly confirm diagnosis in individuals with a family history of ALS. There are currently experimental therapeutic approaches being tested in human pilot studies which are focused uniquely on FALS. ALS Canada funds research to identify and characterize genes involved in ALS.
- Aggregated and secreted proteins | Canadian scientists have been world leaders in this arena of research. About 15 years ago, the observation that mutant SOD1 proteins form clusters (called aggregates) inside of motor neurons opened the door to an entire field of study to understand why proteins clump inside the cells, and what can be done to minimize or prevent this. In the past five years, three of the newly identified FALS genes have also been associated with the formation of such aggregates. Every cell has several mechanisms for clearing mutant or misformed proteins; when these mechanisms do not operate effectively enough in motor neurons, there is degeneration. Candidate therapies to minimize the formation of these aggregates, or to activate the natural pathways inside motor neurons which eliminate problem proteins are currently being developed and one is being tested in early stage clinical trials. Also within the past five years, studies demonstrated that the mutant or misfolded SOD1 protein can be secreted from motor neurons (“in the dish”) and that the protein can then be taken up by adjacent cells. One leading current hypothesis is that this phenomenon may be the basis of the inflammatory process carried out by the glial cells which surround motor neurons, and further, may play a major role in the progression of motor neuron degeneration from one region of the nervous system to another. ALS Canada funds research in the processing of misfolded proteins and in strategies to neutralize mutant proteins after they are secreted from motor neurons.
- Mitochondria | Mitochondria are tiny vesicles found inside all cells of the body. They are the energy generators of the cells. Motor neurons require a lot of energy to communicate signals which originate in the brain to their ultimate target—the muscle. Thus, motor neurons typically contain high numbers of mitochondria. Mitochondria also serve to monitor important molecules which indicate the overall state of the cell’s health; when certain signal molecules are present, cell death pathways are activated. These vesicles have been a constant subject of study with respect to ALS for the past 15 years. The studies continue to confirm the critical role of mitochondria in motor neuron survival and provide more and more sophisticated details about their roles in intracellular regulation. A new clinical trial of a compound believed to be neuroprotective by supporting mitochondria entered Phase III (the final stage of a clinical trial) at the beginning of this year. This very large scale study is taking place at centres in the U.S., Canada, and Europe. ALS Canada funds research to characterize the roles of the mitochondria in healthy motor neuron function.
- Biomarkers | A serious challenge in the treatment of ALS patients is the length of time between first clinical visit related to symptoms, and formal diagnosis of ALS. Diagnosis can take up to 18 months; this period is considered to be an important window of opportunity to slow the progression and protect the motor units which remain functional. Biomarkers to confirm diagnosis or document progression are a goal of several research projects funded by ALS Canada. Examples are studies of mRNA and protein isoforms serving as “barcodes” (Janice Robertson and lab members)—work funded by the NRP and doctoral and postdoctoral fellowships; and use of muscle unit number estimation (MUNE) as a surrogate marker of progression (Sanjay Kalra and Ming Chan)—work funded jointly with ALSA.
We have learned in the past 10 years about ALS confirms that it is a complex disorder involving not only the known target cells (motor neurons) but additional types of cells which can either protect and support the neurons, or lead to disease progression. Thus it is believed that effective treatment will likely involve more than one therapeutic agent, targeting several of the known mechanisms instead of just one. It is important to understand that research breakthroughs can occur at any time, in any of the areas described above, or in additional research fields. Thus it is critical to fund as many projects in parallel as possible, to identify mechanisms and related therapeutic approaches for clinical trial.
To follow through on this, ALS Canada:
- Supports three year full operational grants for established ALS scientists, for (on average) three new lab projects every year
- Works in partnership with other agencies (both federal and private) to maximize the number of ALS projects which can be funded
- Supports the development of young investigators by providing three-year doctoral and postdoctoral fellowships to (on average) three new candidates every year
- Provides seed money for highly innovative projects which bring new methodologies and new researchers into the ALS field
- Provides funding for specialized training of neurologists in clinical research and care of ALS patients
- Enables Canadian scientists and clinicians to share results and discuss research priorities by funding an annual pan-Canadian Research Forum, and by providing travel stipends to the annual International ALS/MND symposium
- Supported the foundation in 2008 of the Canadian clinical trials and research network (CALS) which has 15 Centres across Canada and is currently running its second and third national clinical trials
Supports the establishment of a national ALS Registry as a module of the Canadian Neuromuscular Disease Registry (CNDR) based at the University of Calgary