By Dr. Jim Blackman, Medical Director, Cerebral Palsy International Research Foundation
Stem cell therapy is promising yet there is misunderstanding regarding the current state of its readiness for treatment of cerebral palsy. There are only two institutions in the United States conducting carefully designed research trials of stem cells in cerebral palsy but there are a number of clinics outside the US offering this therapy.
Recently Dr. Luigi Titomanlio and colleagues published an excellent review of stem cell therapy for neonatal brain injury, one cause of cerebral palsy. (Titomanlio L, Kavelaars A, Mani S, et al. Stem cell therapy for neonatal brain injury: Perspectives and challenges, Annals of Neurology 2011;70(5):698-712.) As this review was intended for a medical audience, it is somewhat technical. However, it does explain the many aspects of stem cell therapy and summarizes the current state of knowledge regarding their use. I asked Drs. Gordon Worley and Jessica Sun from Duke University to comment on this article. Afterwards, I will provide less technical comments on stem cell treatment in cerebral palsy and list several excellent on-line sources of dependable information.
This European review of stem cell therapy for neonatal brain injury is written for physicians interested in learning about where we stand now. Background about the five different types of stem cells that are used in animal experiments to treat neonatal injury is provided. These types are neural stem cells, induced pluripotent stem cells, mesenchymal stem cells harvested from bone marrow, and umbilical cord blood stem cells. Each has some advantages and some problems for cell therapy, as discussed in the paper.
Strategies for use of stem cells in newborns are presented. Obstacles that need to be studied are cell dose, timing of transplantation, route of administration (directly into the brain or other), and assessment of mechanism of action. An issue that needs to be determined by animal studies is whether stem cells after injury improve outcome (when they have been shown to) by “paracrine” effects, that is, by secretion of growth and differentiation factors that stimulate endogenous regeneration, or by engraftment (the stem cells themselves forming the neural cell elements). Potential complications of engraftment of some kinds of stem cells are neuroblastoma (with human neural stem cell transplantation), teratoma (with embryonic stem cell transplantation), and acute and chronic rejection (with neural stem cell transplantation).
Clinical trials of stem cell therapy in neonates with brain injury were reviewed. All studies are preliminary. The authors conclude that “based on animal models of hypoxic ischemic encephalopathy, human cord blood cells and mesenchymal stem cells (MCS) may be the most promising stem cells, as they are effective and potentially available for human studies. Human cord blood stem cells have advantages over MCS that may support their use for neonatal insults.”
We at Duke are conducting a clinical trial to evaluate the effectiveness of an intravenous infusion of a child’s own umbilical cord blood in young children with cerebral palsy, ages 12 to 72 months. The safety and feasibility of an intravenous infusion of autologous cord blood in children with acquired brain injuries was demonstrated in a “lead up study” to the clinical trial. The trial is a double-blind placebo controlled study, with crossover at one year. The placebo infusion looks and even smells like the cord blood infusion. Three challenges we have faced in designing a robust trial are: parents willingness to have their children randomized to placebo treatment; defining eligibility criteria that allow assessment of endpoints without unduly limiting enrollment and assessing change due to cellular therapy above what is expected in the development trajectories of children with CP. Gross motor, fine motor, cognitive, and speech and language capabilities are assessed objectively with accepted measures. MRI with DTI and tractography provide objective measures of neuroplasticity. Quality of life is also assessed.
We are actively recruiting subjects to participate in what we consider to be an important study. Interested parents or physicians with potential referrals are encouraged to e-mail Dr. Jessica Sun at firstname.lastname@example.org the Study Coordinator, or Dr. Joanne Kurtzberg at email@example.com for more information.
─ Gordon Worley, MD, Program in Neurodevelopmental Disability and Jessica Sun, MD, Pediatric Hematology and Oncology (Bone Marrow Transplant Service), Duke University.
University of Toronto Newsletter
Dr. Michael Fehlings and colleagues at the University of Toronto have published an online newsletter, aimed at a non-scientific or health professional audience, on stem cell treatments for cerebral palsy (http://www.childhooddisability.ca/cdc_en/newsletter.php). More detail can be obtained at that website. Here are some of the key points:
- 1. Transplanting stem cells into the brain could support and/or replace deteriorating brain tissue during the process of white matter damage in cerebral palsy.
- 2. Animal models used in research on cerebral palsy have shown that many types of stem cells can be used to reduce damage and return motor function after brain injury.
- 3. New technological improvements make it possible for skin cells to be taken from a patient and turned into the exact cell needed to repair injured tissue, getting rid of the need for tissue donor waiting lists and anti-rejection drugs.
- 4. Once stem cells are put in, they can never be removed.
- 5. There are no proven stem cell treatments available for patients with cerebral palsy right now, and it will take a number of years for safe and effective therapies to make it to the clinic.
- 6. Unregulated clinics outside of North America are offering stem cell transplants; however, these clinics have shown no scientific proof that their procedures offer any effect beyond placebo effects and/or normal development.
- 7. Stem cell transplantation would probably have to be performed within the window of time between the first appearance of injury and irreparable loss of neurons.
Here are some excellent websites for information on stem cell treatments that you can trust:
International Society for Stem Cell Research (ISSCR) – A world leader for stem cell research. A very authoritative and helpful source of practical information. http://www.isscr.org/public
U.S. National Institutes of Health – A government-sponsored initiative providing upt-to-date information on stems cells in regenerative medicine. http://stemcells.nih.gov/
Current North American Clinical Trials on stem cells for cerebral palsy – Duke University http://clinicaltrials.gov/ct2/show/NCT01147653
Georgia Health Sciences University http://clinicaltrials.gov/ct2/show/NCT01072370
Reprinted with permission from Cerebral Palsy International Research Foundation