California Lutheran University
Dr. Kenneth O. Long Ph.D.
May 11, 2018
Cerebral Palsy and Stem Cell Therapy
Cerebral palsy (CP) is categorized as a movement disorder affecting muscle tone and posture. According to Carroll and Mays (2011), Cerebral palsy is a heterogeneous group of conditions affecting the cerebral hemisphere and is a non-progressive motor disability. The disease is caused by genetics, infections, metabolic disorders, and prenatal hypoxia among other causes and is associated with different degrees of cognitive abnormalities. According to Chahine et al. (2016), the consequences of cerebral palsy as a condition is a major burden on the patient and his or her family financially and socially. Regarding the disease epidemiology, CDC (2018) estimated that 2 out of 1,000 are born annually with the condition, the same source also indicates that 1 in 323 children are suffering from CP. Reversing the trajectories has been almost impossible because an improvement in neonatal care has little or zero effect on the incidence rates. Researchers have tried to devise different treatment options for the management of CP, for example, physical therapy which aims at improving mobility, strength and flexibility of the victim is recommended. Slaich (2009) has recommended occupational therapy with an increased focus on motor functions, perception and oral motor skills. Regardless of the outcomes of these interventions, it is evident that they do not prevent the occurrence of the diseases.
Modern developments in biotechnology and stem cell research have however paved the way for new treatment approach which if successfully adopted aims at eradicating the condition. The purpose of this research is thus to present the current state of stem cell transplantation for cerebral palsy patients. This paper will review current efforts, cell types that might be used, how the disease affects the brain, the treatment side effects backed with clinical studies.
According to Marret et al. (2013) stem cells refer to somatic cells which can differentiate into different cells. As the body continues to grow, stem cells can specialize and perform specific functions. The two major types of stem cells are the embryonic and adult stem cells. In the latter, the stem cells are mainly involved in processes such as replenishing specialized cells as well as maintaining regular turnover of intestinal, skin and blood tissues. Consequently, in embryonic stem cells (mesenchymal stem cells), can differentiate into all of the specialized embryonic tissues (Marret et al. 2013). This uniqueness of embryonic stem cells has made them suitable for treatment or different diseases and conditions, especially in cases where pharmacological, physical and occupational therapies have proved to have minimal or no effects. There are also Neural Stem Cells (NSCs), which are rapidly gaining favor in clinical studies, especially when it comes to the handling of neurological diseases like spinal cord injuries. Some of the earliest studies seeking to manage cerebral palsy with stem cell therapy were done by Kumar et al. (2009) who used autologous bone-marrow-derived mononuclear cells (BMMNCs) to treat one or more CP patients. From the study, it was noted that the patient recorded significant improvement in the Gross Motor functions. Additionally, there was a significant improvement in their bladder and bowel control. The route of stem cell administration into the body of the patient is normally intravenous or direct injection into the CNS.
CP Etiology and Pathophysiology
Successful management of cerebral palsy using stem cell technology depends on the condition’s aetiology. According to Kurt (2016), potential causes of CP at times tend to vary with prenatal and neonatal groups. Postnatal trauma such as the earlier mentioned examples of infections and toxicities along with encephalopathy are also considered as possible causes of cephalopathy. Another cause of CP, the shaken baby syndrome, which is usually evident in less than one year (when a caretaker takes care of the baby and move him, or her back and forth) can also result CP. Additionally, prenatal and neonatal causes of CP are attributed to prematurity and perinatal problems which in turn result in injury patterns. Prematurity and brain haemorrhages are also associated with the condition, as well as child abuse or nonaccidental trauma. Toxic factors result in brain maldevelopment during the whole pregnancy and after birth, Kurt (2016). According to studies conducted in laboratory animals such as rats, that abuse of drugs such as valproic acid by the mother can cause child’s brain damage thus resulting in non-progressive motor disability thus making the onset of cerebral palsy. Once the child has been born with the condition or he or she develops cerebral palsy after birth, the condition in most cases is irreversible, but improvement can be recorded over time even though such incidences are also rare.
Sources of Stem cells
To understand how stem cell therapy works in the management of cerebral palsy, it is important to highlight some of the potential sources of these cells. According to Sharma (2017), mesenchymal stem cells (MSCs) are derived from bone marrow stromal cells and are capable of hematopoiesis. These cells are also located in human umbilical cord blood. The cells are fibroblastic-like and have the ability for self-renewal. The other source is multipotent adult progenitor cells (MAPC) which are also derived from bone marrow, and the phenotype consists of MHC class I and MHC class II, fetal liver kinase 1 (Flk1)dim and CD44-, CD45- (Carroll and Mays (2011). These cells, on the other hand, develop into mesenchymal cells but with neuroectoderm and endoderm characteristics in vitro. In a clinical study conducted by Velthoven et al. (2013), the efficiency of MAPC was investigated using a rat model with a neonatal hypoxic-ischemic injury. Following the administration of MAPC, positive outcomes were shown positive for transcription factors of human embryonic stem (ES) cells recorded, and the rats had enhanced survival rates. Other sources of stem cells include umbilical cord blood, which is a major source of adult stem cells and Induced pluripotent stem cells (iPS cells). Oligodendrocyte progenitor cells (OPC) on the other hand are obtained from fetal brain tissue. OPC can be derived from human embryonic stem cells showed significant health improvement in an acute model.
Possible Stem Cells Modes of Action
Researchers have not been able to successfully understand the mechanism of stem cell in transplantation for cerebral palsy. However, one of the main ideas inherent in stem cell transplantation is that when utilized for cerebral palsy treatment it replaces the cells of the damaged nervous system. Other researchers are still skeptical with regards to the efficiency of adult stem cells to sufficiently restore and ensure successful functionality of the nervous system to normal (Velthoven et al. (2013). Embryonic or iPS cells have greater potential for replacement of the nerve cells when the number of cells involved is limited in vivo. This suggestion of cell replacement as a mode of action of stem cells in the management of cerebral palsy has been refuted on the basis that it is not supported by the current knowledge, which already exists regarding the nature of stem cells (Velthoven et al. (2013).
Another theory suggests that there is a possibility that the transplanted stems cells used in the management of cerebral palsy differentiate into microglia or astrocytes. According to Thiet (2016) glia are essential when it comes to brain functioning, especially during developments in adult brains. The introduction of both astrocytes and microglia is thus critical during brain development. The dynamic aspect of microglia cells allows them to scan their environment both physiologically and pathologically and can regulate tissue homeostasis through scavenging functions. Astrocytes, on the other hand, are derived from neuroepithelial cells and have the ability to differentiate into Mature cells. Even though it is evident from the above explanation that both astrocytes and microglia originate from transplanted differentiated cells, how this would assist in functional recovery following cerebral palsy is still unclear.
Another explanation on how these cells work include that bone-marrow-derived cells are the ones, which participate in blood vessel regeneration Thiet (2016). This is achieved because of the adhesive properties of CXCR4-positive cells onto vascular endothelium. CXCR4-positive cells regenerate tissues mediated by hypoxic gradients through HIF-1-induced expression of SD-1. This was demonstrated by Borlongan et al. (2004) who demonstrated that crude bone marrow could form endothelial cells in an animal model of stroke. The other suggestion on how stem cells help in the management of cerebral epilepsy included that the transplant can induce greater survival of intrinsic cells. This theory was confirmed in one study conducted by Mahmood et al. (2004) who used MSC injection to show that the transplanted stem cells could increase the expression of brain-derived neurotrophic and nerve growth factors following a traumatic injury. Even though this evidence appears convincing, it can only be applied to post-injury period disease and condition management.
Lastly, another explanation was elaborated in Crompton et al. (2014) who aimed at highlighting the effects of adult stem cells on splenic function following an acute brain injury. In this study, umbilical cord blood (UBC), which is also a popular source of adult stem cells could lessen the splenic release of inflammatory cells and thus be able to protect the brain. Their research was supported by another study carried out by Borlongan et al. (2004), which recorded positive results for intravenous injection of MAPC for splenic response to injury.
Cerebral Palsy and Stem Cell Therapy
In almost all incidences of CP, the major similarity is the lack of oxygen and blood in the brain during fetal development or at childbirth i.e., hypoxic-ischemic insult. Following a hypoxic-ischemic insult, blood vessels in the regions, are also tasked with carrying motor neurons which are fragile at usually at a higher risk of blocking and thus result in reduced blood flow. Specifically, the oligodendrocytes are more likely to be damaged. Any damage or death to the oligodendrocytes means loss of electrical signals throughout the body because the neurons remain unprotected and they eventually degrade and die due to the absence of the myelin (Kurt, 2016). The best treatment option is, therefore, one, which aims at replacing myelin white matter before neuronal death. Considering the properties of stem cells, they could even be an effective means of treatment for the injury because of their degenerative properties.
Chahine et al.’s (2016) article “Treatment of Cerebral Palsy with Stem Cells: A report of 17 cases” is a report of 17 patients diagnosed with CP who were treated with intrathecal administration of Bone Marrow Mononuclear Cells (BMMC). Six to eight puncture sites were identified on the patient and used to aspirate the bone marrow. The evaluation criteria for the patient was based on their motor skills, and their cognitive abilities. On a procedural day, the bone marrow was collected in the operating room, washed and separated using density gradient configuration method. Microscopic techniques were used in the process of bacterial characterization. For seventeen patients suffering from CP, the study indicated that average improvement was 1.3 levels with their cognitive improvement as well.
Although stem cell technology has not been approved as a treatment option for the general public, several clinical tries are in progress. For example, in the United States, there is an ongoing clinical trial in Duke University and in the Medical College of Georgia. The details of the studies and their clinical phases are listed in clinicaltrial.gov. One of the recent and very promising studies is sponsored by Vinmec Healthcare System, and the lead investigator is Liem T Nguyen. The aim of the study is to assess the safety and effectiveness of bone marrow mononuclear stem in patients who have cerebral palsy. There are 40 study participants involved, and the research is currently in its second phase. After successful completion researchers will be in a position to determine if the stem cell approach will be the solution to this major health problem which has continued to cause pain as well as economic and social problems to its victims.
In an interview with Neurology Physician Dr. Moussa Heikali, M.D. of Encino, California; ongoing clinical research studies on Stem Cell Therapy had been examined by Dr. Heikali since early 2015. By mid 2017, he began his clinical trials for testing patients with CP. According to Dr. Heikali, so far only one patient, a young male, 27 years of age has been tested with autologous stem cell transplantation (stem cell therapy). The patient was given six sessions of the therapy, one session per month for six months straight, and according to Dr. Heikali has displayed improvements in some fine and gross motor skills, as well as in psychological behavior. “The patient has felt more energy, is walking better, and has become less depressed” (Dr. Heikali, 2018). However, there were some temporary and minor side effects from the therapy caused to the patient that had displayed reactions. Some of the reactional side effects were muscle aches, chills, and a slight fever. However, the side effects are not from the current therapy itself, but are instead from the preservative inside the umbilical cord blood of the autologous cell for transplantation, in which is what keeps the cells preserved from expiration. Thus, the preservative is needed to keep the cells alive and usable. If less of the preservative is injected in the patient, then the patient will have and show less side effects (Dr. Heikali, 2018).
Although the patient has shown some improvements, there is still no significant improvement since the therapy was given to the patient. Efficacy rates are still very low between 25-30% where only non-major improvements have been made. According to Dr. Heikali clinical trials will still be undergoing testing, and the next future clinical trial tested on a CP patient will proceed on May 18, 2018. From there on future studies will be performed where autologous stem cell transplantation is yet to show any further hopeful improvements as a result from the oncoming patient (Dr. Heikali, 2018).
According to Clinicaltrial.gov. the University of Texas Health Science Center in Houston in collaboration with Let’s Cure CP foundation, cord blood registry Inc. and Mission connect also sponsored one research project with the sole purpose of comparing the safety and effectiveness of stem cells of banked cord blood or bone marrow (Crompton et al. 2014). The study participants were children between ages 2 to 10 years with CP. The study is also in its second phase, and researchers are optimistic that findings from this research will enable scientists to devise the best treatment approach, which has little or no unwanted effects on patients. When it comes to answering the question of how much one can improve an individual’s disability from Cerebral Palsy and if the treatment approach guarantees one full recovery, international reputable organizations such as EuroStemCell claim that it has proven successful in reducing brain damage and side effects. However, due to the complexity of the human brain and the fact that it is not well understood especially when it comes to cell loss and damages, scientists are finding it difficult to try some of these studies performed in animals in human beings because they have different outcomes. Currently, it is evident that stem cell therapy cannot be used to treat an infant or anyone with CP. Majority of the studies are still in their clinical trial phase. Once the research is out, it is, however, likely that stem cell therapy will have to be supplemented with physiotherapy and physical therapy. In most of the ongoing studies, bone marrow-derived mononuclear cells (BMMCs) have proved to be more helpful in cerebral palsy especially when it comes to improving motor functions, cognitive and sensory capabilities and in speech capacities. Additionally, research also noted improvement when it comes to bladder and bowel control.
One of the main risks associated with stem cell therapy in the management of cerebral palsy is graft-versus-host disease. This mainly occurs primarily with allogeneic transplants. Children undergoing hematopoietic stem cell transplantation because of malignancies tend to have high incidences of graft-versus-host disease because they also receive immunosuppressive medications, chemotherapy as well as radiation therapy in addition to the actual stem cell treatment. These individuals are also likely to contract infections such as herpes or cytomegalovirus, and this is often associated with a weakened immune system, which leaves the body vulnerable to infections and disease-causing microbes. In another study, it was also discovered that patients undergoing stem cell therapy tend to develop complications such as Herpes virus-6 encephalitis especially if there was unrelated umbilical cord transplant (Kurt, 2016).
As researchers continue to carry out more studies to determine the efficiency of stem cell therapy in cerebral palsy treatment, there is need to acquire more knowledge on the different types of stem cells. Particularly, more research needs to be done to understand about cell differentiation strategies and methods of intrinsic neural proliferation. To have more generalizable and reliable findings, research should also focus on controlled clinical trials, which should be conducted taking into consideration the differences between cerebral palsy patients. Additionally, since it is not possible to diagnose CP in infants who are less than six months, robust diagnostic approaches should be devised to allow for early treatment after the successful development of an intervention.
Based on this research, it is evident that the development of cerebral palsy is due to series of events which occur in the brain of the victim during development stages. Many of these events include congenital abnormalities in genetic factors. Genetic polymorphisms in coagulation or vascular endothelium factors of the placenta, for instance, are associated with the condition. Other contributing factors include infections such as syphilis and Cytomegalovirus (CMV), Herpes simplex virus among others. Vascular disease of pregnancy and preterm birth also increase one’s susceptibility to the condition. Through development in biotechnology and stem cell technology to be specific, researchers have been able to identify specific degenerative cells and modify them to treat the condition. Although the exact mechanism of action of these stem cells is not well understood, future studies have been developed by researchers who have come up with different suggestions including replacing the damaged cells among others.
Currently, future studies have also examined stem cell therapy for other diseases and conditions in order to understand the neurological mechansims behind these other conditions that could possibly help answer some of the unknown underlying questions in the use of stem cells for cerebral palsy that are still ongoing in research to scientists. Many of the diseases being studied include: Parkinson’s, Dimensia (Alzheimer’s), Rhemeutoid and Osteo-Arthritis, Diabetes Type 2, Muscular Scerosis, Lupus, Kidney disease, Liver disease, COPD, ALS, Spinal Cord injuries, Autism, Prostate disorders, Sexual Dysfunction, Crohn’s disease, Ataxia, Muscular Dystrophy, allergies, Heart Conditions, Acne, and etc. (Swiss Medica Clinic, 2018).
Studies for almost all diseases are still in the developmental stages and are continuously undergoing clinical trials. Existing journals have shown that some CP patients subjected to the treatment during the trials phases recorded positive outcomes especially in areas such as motor control. In the United States, the research is ongoing, and studies will continue to aim at testing the effectiveness of the intervention and minimizing the risks associated with this treatment approach.
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