Post #20 in our 30 Days of Inspiration, Information and Motivation series marking National Cerebral Palsy Awareness month.
Today’s post comes from Canada via Dr. Crystal Ruff, PhD and Dr. Michael Fehlings, MD, PhD, FACS, FRCSC
Of all the questions surrounding potential future treatment of Cerebral Palsy, the questions we hear most often these days primarily deal with stem cells. Do they “work”? Will stem cells improve or “cure” CP? Is any of the current stem cell research being done now showing promise? Aren’t there different kinds of stem cells?
We are very fortunate to have several leading physicians and scientists with an interest in stem cell research on our RFTS Medical Advisory Board. One of those stem cell research scientists is Dr. Crystal Ruff, PhD, who works with Dr. Michael Fehlings, one of the leading stem cell researchers in the world.
We asked Dr. Ruff and Dr. Fehlings if they would be willing to give us the “straight scoop”, as they see it, regarding the current state of stem cells as it relates to Cerebral Palsy. We thought you would find this information both very educational and practical.
Dr. Michael Fehlings is the Medical Director of the Krembil Neuroscience Center and heads the Spinal Program at
the Toronto Western Hospital, University Health Network. Dr. Fehlings is a Professor of
Neurosurgery at the University of Toronto. He holds the Gerald and Tootsie Halbert Chair in Neural
Repair and Regeneration, is a Scientist at the McEwen Centre for Regenerative Medicine, and is also a
McLaughlin Scholar in Molecular Medicine. In the fall of 2008, Dr. Fehlings was appointed the
inaugural Director of the University of Toronto Neuroscience Program and Co-Director of the
newly formed University of Toronto Spine Program.
Dr. Fehlings combines an active clinical practice in complex spinal surgery with a translationally-
oriented research program focused on discovering novel treatments for the injured brain and spinal
cord. This is reflected by the publication of over 400 peer-reviewed articles chiefly in the area
of spinal cord injury and complex spinal surgery. Dr. Fehlings leads a multi-disciplinary team of
researchers which is examining the application of stem cells, nanotechnology and tissue engineering strategies
for spinal cord repair and regeneration. He is also a principal investigator in the Christopher
and Dana Reeve Foundation North American Clinical Trials Network (NACTN), is co-chair of the
internationally renowned Spine Trauma Study Group and leads several international clinical research
efforts through AOSpine.
Dr. Crystal Ruff is a keen investigator in the field of regenerative neuroscience and translational research, with a proven track record of academic and performance excellence. After graduating Summa Cum Laude with an Honours BSc in Biochemistry and Molecular Biology from McMaster University, she completed her PhD in Neuroscience at University College London (UCL), with the Director of Perinatal Brain Repair.
Dr. Ruff is currently applying this knowledge gleaned abroad to North American paradigms during her post-doctoral fellowship in the Fehlings lab, spearheading the stem cell therapy for Cerebral Palsy animal initiative in association with the NeuroDevNet NCE. While at UHN, she has earned the Freedman Postdoctoral Fellowship, the Ontario Stem Cell Initiative International Postdoctoral Fellowship, as well as several national and international first place research-based awards. Her work investigates the potential for stem cells to functionally remyelinate the injured or dysmyelinated brain.
Her work in knowledge translation of stem cell and regenerative medicine involves several internationally-distributed documents, as well as information packages produced for the White House Office of Science and Technology Policy working group and CTV news. She has also produced oral presentations on stem cell therapy, including a keynote speech on the reality of stem cell treatments for CP for the Pediatric Division of the Canadian Physiotherapy Association at their annual meeting.
Stem Cells: The Hype, The Hope and The Reality
By Dr. Crystal Ruff, PhD and Dr. Michael G. Fehlings, MD PhD FACS FRCSC
Project funded by the NeuroDevNet Networks of Centres of Excellence and Ontario Brain Institute
Dr. Ruff has been funded by the Freedman Postdoctoral Fellowship and the Ontario Stem Cell Initiative International Postdoctoral Fellowship
What is CP?
Cerebral Palsy (CP) is the most common developmental disorder and affects approximately 2.5 out of every 1000 live births. It is caused by damage to the brain that disrupts how the brain sends signals to the muscles telling them to move – resulting in impaired movement. Depending on the location, damage to the brain can also have an effect on other brain functions, such as vision, hearing or cognition.
Now, to understand how we can use stem cells for CP, we have to understand how CP works in the brain. Cells in the brain, called neurons, send signals to muscles, similar to an electrical signal along a wire. Just as electrical wires need an insulated coating to work properly, neurons have long “wires,” called axons, which must be insulated with a substance called myelin for them to function properly. Myelin is produced by specialized cells called oligodendrocytes, which also reside in the brain.
In CP, damage to the developing brain occurs when the access of oxygen to the brain is disrupted, resulting in specific oligodendrocyte and also neuronal death. Neuronal death is similar to removing the electrical wires completely – meaning that no signal will reach a muscle. Oligodendrocyte death, called “demyelination,” is similar to removing the insulation on the wire, although the axonal wires remain intact, signals become weak and can get lost. Weak signals to muscles lead to muscle wasting or spasticity. Depending on how severe the damage is, there can be numerous neurons and axons affected, resulting in the impairment of multiple muscles and functions.
Importantly, many neurons that survive have had their insulating myelin removed, and this is where stem cell therapy for CP potentially comes in. In the lab, and in some adult diseases that show demyelination, scientists can replace this myelin insulation by transplanting stem cells that can make oligodendrocytes. There are also other types of stem cells that might be able to strengthen existing connections and temporarily improve the injury environment.
What is a Stem Cell?
As a general definition, a stem cell describes a cell that can be influenced to change into one or more types of more specialized, or “differentiated” cells. Stem cells can also “self-renew”, or make identical copies of themselves and generally have enhanced growth capacity compared to fully differentiated cells. By using certain chemicals and techniques, scientists can push a single stem cell to develop into one or more of a cell type you would find, for example, in the brain of an adult. Some drugs can also be used to strengthen stem cell populations that already reside in adult tissue. There are lots of different types of stem cells, all with different properties and sources, depending on which tissue they are sourced from. The most primitive stem cell that can turn into any cell type in the body is called a pluripotent stem cell. Other, more mature stem cells reside in adult tissue and can differentiate into a more limited number of cell types. We have created an excellent resource on the development of stem cells that can be found on www.drfehlings.ca under the knowledge translation section.
Here are some important points to remember about stem cells:
- Not all stem cells are derived from an embryo or cord blood– indeed, adult stem cells reside even in mature tissues, although they cannot divide into as many different cell types.
- Based on its source, a cell will only naturally differentiate into certain types of sub-cells. For example, neural precursors (NPCs) become brain cells and mesenchymal cells (MSCs) become muscle, bone, blood, connective tissue (and other mesenchymal types), but not neurons.
- ALL stem cells currently under investigation for neural repair are more adult types; if a pluripotent cell is injected into the brain, there is no way to predict which of many cell types it will become (you do not want bone developing in your brain, for example). So, for transplant experiments, cells are used which can only become 1 or 2 types of specialized cells in the body.
What can Stem Cells do for CP?
While there are many different types of stem cells, Neural Precursors (NPCs) are the cells we use in our lab as part of our NeuroDevNet and Ontario Brain Institute projects. These cells can turn into oligodendrocytes, which can replace the myelin insulation on axonal “wires,” when introduced in animal brains. Additionally, we have found that these cells are safe in animal models (no cancer formation found yet in almost 10 years of study).
Although, if they are transplanted into a child, they would need to remain safe for much longer than 10 years, with no unforeseen side effects, as this is a permanent cell replacement option and these NPCs could never be removed. So, this strategy remains imperfect, but very promising. Scientists have made cells for animal transplant better, and are just starting to transplant human NPCs into humans, but most trials are beginning in older populations. The first NPC trial in children has been started by StemCells Inc, using NPCs from the fetal brain (that ethical issue is not yet overcome in most human NPC trials) to target Batten’s Disease, a normally lethal genetic disorder of childhood. While promising, the safety and efficacy of these cells have not been proven in clinical trials yet; further study is needed to optimize this strategy both technically and ethically.
Recently, a new way to generate pluripotent stem cells from mature skin cells was discovered. The generation of these cells – called induced pluripotent stem cells (iPSCs) – was first described by Shinya Yamanaka (who recently won a Nobel prize for this) and was later improved upon by our collaborator, Andras Nagy (Mount Sinai Hospital in Toronto). To avoid having to isolate NPCs from the adult brain, which is obviously invasive, the Fehlings lab, along with collaborators Derek van der Kooy, Cindi Morshead and Andras Nagy, have recently been able to make NPCs from these iPSCs. The safety and effectiveness of these cells are currently being tested in our lab in various animal models of brain injury. Interest in this industry has led to explosive growth since iPSCs were first discovered in 2006. The first clinical trial using patient-iPSC-derived retinal cells for age-related macular degeneration was granted conditional approval for a clinical trial in Japan in late February, 2013.
Nonetheless, there is a stem cell type that has been used in humans safely for decades and that is also being explored in CP trials. Mesenchymal stem cells, or MSCs, are used clinically for bone marrow transplants in Leukemia. Unlike NPCs, MSCs do not become remyelinating cells, but there is some evidence suggesting they can secrete chemicals which might stimulate axon growth (for better or worse – since pain nerves can also be stimulated). Likewise, they can dampen some potentially harmful inflammatory processes and increase blood supply to the tissue.
Furthermore, there is some evidence that the chemicals they secrete can attract neural precursors that are in the brain already. However, supporting evidence for these findings is generally quite inconsistent. Furthermore, most animal evidence indicates that these cells are cleared out by the body within a few weeks, making any potential benefit very short-lived.
If you search “stem cells” and “cerebral palsy,” the first sites to come up are “clinics” abroad claiming to be able to “treat” several conditions with “stem cell therapy” for several tens of thousands of dollars and with no to few negative side effects. It is important to note, there is currently no clinically proven stem cell replacement therapy for CP and people should use extreme caution. The reason all of these clinics are abroad is because it is illegal for them to offer these “services” in most developed countries.
Furthermore, receiving “treatment” from one of these non-compliant clinics abroad will usually exclude you from receiving a legitimate clinical trial at home. These “medical tourism” ploys should be avoided until a facility produces a credible clinical trial that is approved or recognized by a health authority such as Health Canada or the Food and Drug Administration (FDA) in the U.S.
It should be said that stem cell therapy (in the form of bone marrow transplant) is effective and is used routinely for blood diseases like Leukemia, but has not been approved or proved useful in humans for Cerebral Palsy. Clinical trials using MSC stem cells are beginning for children with CP, as MSCs are the “safest” cell type. MSC stem cells can be derived cheaply and safely and they are quickly cleared by the body’s immune defences, although they do not show consistent benefit in animal models. In animal models, it seems that NPCs, which the Fehlings group explores, show the most promise for permanent myelin replacement. However, these cells are not yet in clinical trials for children with CP.
What are the Current Clinical Trials for CP? What Trials use NPCs?
Currently, stem cell therapies are only in the clinical trial phases – that means you will never be asked to pay for a legitimate stem cell trial. There are 8 studies currently exploring supporting MSC cells, one of which has reported positive results. There are currently no NPC trials for CP, although most studies in the central nervous system (CNS) are exploring NPCs for spinal cord injury and stroke in adults. Importantly, the first clinical trials using NPCs in children are underway, using them in children with rare, lethal genetic disorders. You can find a summary list of these on the Fehlings website: www.drfehlings.ca or you can search clinicaltrials.gov. Legitimate clinical trials are required to register with the website clinicaltrials.gov if they want to have FDA approval, or if they want to publish their results in respected medical journals. So, if you are looking for more information on real treatments and clinical trials, or would like to become involved, look there first.
Where can I Find More Information?
Reaching for the Stars – Check out our section on stem cells in the website resources section.
Fehlings Lab Website – We are one of the world leaders in stem cell and regenerative medicine and have a strong knowledge translation arm with several information documents
NeuroDevNet – Canada’s Leading Consortium on Neurodevelopmental disorders, with several documents on stem cell therapy in the knowledge translation section.
Global 16×9 “Selling Hope” – An excellent investigative news report on the realities of the “stem cell therapy” business.
Clinicaltrials.gov – Website providing current information on ALL legitimate, registered clinical trials.
International Society for Stem Cell Research (ISSCR) – A world leader for stem cell research with a wealth of educational material.
Canadian Institutes of Health Research – CIHR Stem Cell Research page provides up-to-date information on stem cell governance & legislature.
National Institutes of Health Research – A government-sponsored initiative providing up-to-date information on stem cells in regenerative medicine.
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