Update on Stem Cell Research and Potential Treatments for ALS
August 6, 2004
Stem cell research is receiving increasing attention, particularly in many public forums and in the current debates leading up to the November presidential election. The staff and volunteers of The ALS Association share the sense of urgency to develop effective treatments for ALS and we are encouraged by what is being learned from stem cell research. ALSA is in contact with investigators to advance the efforts toward appropriate stem cell clinical trials as the body of scientific knowledge about stem cells grows. In addition, excitement about the potential of stem cell replacement in ALS was heightened with recent reports about a stem cell treatment for ALS patients in China . It is important to realize that within the scientific investigator community the excitement and research efforts into stem cells is continuous with many new studies initiated by different laboratories and top investigators. ALSA has recently funded two new studies in stem cell research and continues to fund leading investigators in different areas of stem cell biology. For more information, view these two articles on ALSA’s web site.
These projects include the use of a variety of different stem cell sources which will be emphasized in the following brief report. Laboratory results are encouraging but scientists recognize the need for rigorous pre-clinical research to move the field forward and increase the potential for success as a therapy for ALS.
New Treatment Reported in China
In a recent media report and in a biweekly newspaper for life science professionals, The Scientist, Chinese neurosurgeon Huang Hongyun describes his treatment approach in patients with ALS as well as other neurological disorders. Dr. Huang uses olfactory ensheathing glial cells extracted from olfactory bulbs from aborted fetuses. Unlike the stem cells described below in the study by Dr. Martin derived from the olfactory bulbs, these cells do not differentiate into neurons. Dr. Huang indicates that the transplanted cells do not replace neurons but are likely to improve the environment for the dying neurons by providing trophic factors. Although interesting and potentially promising, there is currently no published data supporting his ALS work and no human clinical trials. It will be important to observe whether the beneficial effect reported in the ALS patients persists. Follow up discussions with Dr. Huang have been initiated and the potential for appropriate clinical trials is being considered.
Stem Cells Can Become Motor Neurons
From previous reports it has become evident that mouse and human embryonic stem cells, given the appropriate factors, can become motor neurons. For more information, view the article on ALSA’s web site http://www.alsa.org/research/grant.cfm?id=166 The ability for these newly generated motor neurons to form the appropriate connections and hence improve muscle function remains a challenge to achieve. Dr Zhang is exploring the ability of these transplanted neurons to form appropriate connections by introducing them initially into chick embryos as the transplant technology is well established in this animal system. Should this study succeed, the investigators will then transplant the motor neurons into the rat model of ALS to determine whether this approach can alter disease onset and progression. Recently Dr. Tom Jessell, of Columbia University , demonstrated that mouse embryonic stem cells differentiated into motor neurons were indeed able to integrate in the chick embryo.
Surrounding Cells May Protect Motor Neurons
Studies in the past year have demonstrated that the use of stem cells need not be limited to replacement of motor neurons. The introduction of surrounding support cells such as the astrocytes may be beneficial to provide trophic support and improve glutamate uptake, sparing motor neurons from dying. For more information, view the article on ALSA’s web site. http://www.alsa.org/news/article.cfm?id=236
Adult Stem Cells as Potential Treatment for ALS
In an approach to determine whether adult stem cells can be used therapeutically for ALS, Dr. Lee Martin at Johns Hopkins School of Medicine, explored the use of olfactory neural stem cells. These are an abundant source of stem cells in the adult brain which have the capacity to become cells that are motor neuron-like. To test the feasibility of this source, he is currently isolating these stem cells from transgenic mice expressing mutant SOD1 and transplanting them into this same mouse model. In addition, he is transplanting stem cells from healthy control mice and transplanting these into the mouse model for ALS. His early data show that the transplants survive and develop into a variety of cell types including motor neuron-like cells. He is now determining whether they can alter the course of disease in the mouse model.
Current ALSA-Funded Stem Cell Research
Autologous Stem Cell Therapy for ALS
Martin, Lee , PhD
Johns Hopkins School of Medicine, Baltimore , Maryland
http://www.alsa.org/research/grant.cfm?id=137
Recruitment of Replacement Cortico-spinal Motor Neurons via Induced Neurogenesis and Enhanced Survival
Macklis, Jeffrey D., MD, DHST
Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts
http://www.alsa.org/research/grant.cfm?id=134
Regulation of the Expression of the Proneural Gene Neurogenin2 in the Adult Spinal Cord
Guillemot, François, PhD
Division of Molecular Neurobiology, NIMR, London, England
http://www.alsa.org/research/grant.cfm?id=111
Generation of Human Motor Neurons from Stem Cells
Su-Chun Zhang, MD Ph.D.
University of Wisconsin, Madison, WI
http://www.alsa.org/research/grant.cfm?id=166
Stem Cell Therapy for ALS
Clive Svendsen, PhD
University of Wisconsin , Madison , Wisconsin
http://www.alsa.org/research/grant.cfm?id=183
Additional Resource:
Stem Cell Primer
http://www.alsa.org/research/stem_cells.cfm?
Stem Cell Research Talking Points
The stem cell field of research is one that has received much attention over the past few years. It is an area of research that offers enormous potential and hope yet has associated with it key ethical and medical issues.
What are stem cells and where are they found?
- Stem cells are cells that have the ability to divide for indefinite periods in culture and give rise to multiple specialized cell types.
- Embryonic stem (ES) cells can develop into any of the tissues that form the body and are considered to be pluripotent. Earlier studies focused on mouse ES cells, however recently scientists have shown that they are able to isolate and propagate human embryonic stem cells in culture. This breakthrough has fueled much excitement with the hope that the use of human stem cells may reduce the chances of tissue rejection after transplantation. However, as these cells are derived from human embryos, several organizations have opposed these studies.
- Pluripotent stem cells undergo further specialization into multipotent stem cells that give rise to cells with a particular function. For example, multipotent stem cells in the brain give rise to different neuronal cell types and glia.
- While stem cells are important in early human development, they persist into adulthood. Their function in adulthood is less clear. The presence of bone marrow stem cells in adults has been known for a long time. These stem cells give rise to all cells of the blood system. More recently, stem cells have been discovered in the adult brain and spinal cord.
Stem Cell Therapy in Neurodegenerative Disorders
- Insult to the adult central nervous system is devastating because of the inability of central neurons to regenerate and form appropriate connections to restore function. The consequences of insults to the brain and spinal cord are not just a break in communication between healthy neurons and their target, but a cascade of events that can lead to cell death. The discovery of stem cells that can differentiate into neurons has opened up new doors for potential brain “repair” either through stimulation of stem cells resident in adult brain or through transplantation methods.
- Human trials for neuronal transplants have been completed for Parkinson’s disease and stroke. (Note these cells are already differentiated into neurons and are no longer stem cells). In a trial for Parkinson’s disease, functional improvement (as assessed by improved well being of the patients) was seen in 85% of younger patients with transplanted human embryonic dopamine neurons, but no improvement in patients greater than 60 years of age. In 15% of the younger patients adverse symptoms were detected (increased jerky movements) a year after the cells had been transplanted. The number of cells transplanted may be critical as over production of dopamine (the chemical normally released in this brain region and deficient in Parkinson’s patients) is likely to be the cause of the adverse side effects. This study highlights one of the challenges using stem cell therapy for Parkinson’s disease requiring further investigation.
- There are no published human studies of stem cell or neuronal transplants in ALS, although several investigators have published studies showing a slowing in disease progression in transgenic mice expressing the G37R SOD1 mutation. Issues of delivery in patients with ALS, for example, site of delivery, how many cells to introduce and what are the side effects are some of the unanswered questions that scientists take into account when considering clinical trials using stem cell approaches. It is not evident that motor neurons can be replaced to form appropriate connections and it is likely that increased survival in the mouse studies is due to a trophic effect of the stem cells.
Challenges Facing Stem Cell Therapy in ALS
- The discovery that human embryonic stem cells can be isolated and propagated in culture with the potential of developing into all tissues of the body is a major breakthrough for the field. However it has raised a great deal of ethical questions. The NIH currently funds research using embryonic stem cells, however funding is restricted to cell lines that are approved under the NIH guidelines and one of the major concerns amongst investigators is the limitation of these cell lines and the need to generate new more appropriate cell line. There are several efforts underway within the U.S. and abroad to develop new lines outside NIH funding. An intriguing discovery is that bone marrow cells (which are able to develop into all the cells of the blood system) transplanted into mice can migrate into the brain and develop into cells that appear to be neurons. These studies remain controversial however, as scientists dispute the capacity of these bone marrow cells to efficiently generate neuronal like cells. They may be effective however in providing the necessary trophic factors for motor neuron survival. Studies continue in this field and, if successful, this would be the most convenient source for stem cell therapy.
- The mechanism of motor neuron death in ALS remains unclear. It is not certain that transplanted stem cells are resistant to the same insult(s) causing motor neurons to die and stem cells may need to be modified to protect against the toxic environment. Embryonic stem cells in culture can be genetically modified. An attractive use of stem cells is as a vehicle to deliver genes and other factors to dying motor neurons. More research is needed in this area.
- Despite encouraging data that transplanted fetal cells can survive over long periods of time in the damaged area, few studies have shown functional recovery of neurons (neurons making appropriate contact with their target).In addition, unlike Parkinson’s disease where functional improvement is less dependent on appropriate neuronal connections, motor neurons have a huge challenge to form connections with their target (muscle) over a very long distance.
- The presence of neural stem cells in the adult brain and spinal cord may provide an alternative to transplantation eliminating the issues of tissue rejection. If there were a way to stimulate resident stem cells to replace dying cells, the limitations of transplantation could be overcome. Small biotech companies are pursuing this direction in the hope of finding therapeutic compounds that will do this. Further research into molecules and genes that govern cell division, migration and specialization is needed, ultimately leading to new drug targets and therapies for ALS.
