Stem cell therapy has been found to be one of the most effective treatments for children with neurological disorders including CP. Several studies have demonstrated the effectiveness of stem cell therapy in improving gross motor function, muscle tone, spasticity, development and quality of life in patients with CP. Stem cell therapy has also been shown to reduce brain inflammation, increase whole brain connectivity and activate motor regions of the brain.
Based on the early human clinical trials there appears to be a strong argument for the safe and effective use of intravenous stem cell therapy in the treatment of CP. While we wait for phase II/III trials the current data is encouraging and supports use of stem cell therapy in the clinical setting.
Below we highlight and summarize selected trials demonstrating the safety and efficacy of stem cell therapy in children with CP. All of the selected studies used intravenous administration as the delivery route but used different cell types and tissue types. We also include systematic reviews/meta-analysis for additional evidence.
A Randomized, Placebo-Controlled Trial of Human Umbilical Cord Blood Mesenchymal Stem Cell Infusion for Children with Cerebral Palsy (Huang et al 2018)
In 2018 Huang et al conducted a randomized, placebo controlled trial to assess the safety and efficacy of intravenous infusions of umbilical cord blood derived mesenchymal stem cells (UCBMSCs) in children aged 3-12 years old with CP. Children assigned to treatment group received 4 intravenous infusions and basic rehabilitation therapy whereas the control group received intravenous saline and basic rehabilitation therapy. Safety was assessed using laboratory tests, physical examination, electroencephalogram (EEG), routine MRI and incidence of adverse events. There were no significant changes in laboratory results and physical examination. MRI results showed no sign of cerebral tumor formation and minimal improvements in cerebral structures. EEG results indicated that cerebral electrophysiology might be improved after stem cell infusion. No serious adverse events were observed during the 24 month follow up. Upper respiratory tract infection and diarrhea were the most frequently reported non-serious adverse event, none of which influenced the study. Efficacy was evaluated using two standardized assessment tools; Gross Motor Function Measure scale (GMFM-88) which evaluates gross motor ability in 5 functional areas and Comprehensive Functional Assessment scale (CFA) which evaluates function in 5 different functional areas. In the treatment group, total GMFM-88 score was significantly improved when compared to baseline at all-time points during the 24 month follow up period. Individual scores of all 5 functional areas had an upward trend at 3 months. Similarly, total CFA score was greatly improved at all-time points when compared to baseline and when compared to control group. Individual scores of all 5 functional areas also improved at 3 months. These results showed that both gross motor abilities and comprehensive function were improved by stem cell therapy in children with CP. Huang et al concluded that “hUCB-MSC infusion with basic rehabilitation was safe and effective to improve gross motor function in children with CP.”
Effect of Autologous Cord Blood Infusion on Motor Function and Brain Connectivity in Young Children with Cerebral Palsy: A Randomized, Placebo-Controlled Trial (Sun et al 2017)
In 2017 Sun et al conducted a double-blind, placebo-controlled, crossover study to assess the safety and efficacy of a single intravenous infusion of autologous umbilical cord blood (aUCB or ACB) in children aged 1 to 6 years old with CP. Children were randomly assigned to receive ACB or placebo at baseline then 1 year later received the alternate infusion. Cell dose was not uniform and was based on number of cells available from each ACB unit and body weight. Cell dose ranged from 10-50 million cells/kg of body weight and the median dose was 20 million cells/kg. Stem cell therapy was safe and well tolerated without serious adverse events. One patient experienced an infusion reaction to both placebo and ACB treatment which consisted of hives and low grade fever. The reaction resolved with additional anti-histamine medication. Efficacy was evaluated using standardized assessment measurement tools including Gross Motor Function Measure (GMFM-66) and Peabody Development Motor Scales (PDMS-2). Brain MRI was used to evaluate total brain connectivity. Children treated with ACB above the median cell dose demonstrated statistically significant and clinically meaningful improvement in GMFM-66 after 1 year post treatment. Similarly, children who received a dose above the median dose had statistically significant improvement in PDMS-2. MRI results showed a significant greater increase in normalized whole brain connectivity 1 year after treatment in children who received a cell dose of above median dose. This increase in brain connectivity was correlated with improvements in gross motor function. Sun et al concluded that “results of this trial suggest that when dosed >2×10^7 cells per kg, an IV infusion of ACB improves whole brain connectivity and motor function in young children with CP.”
Concise Review: Stem Cell Interventions for People with Cerebral Palsy: Systematic Review with Meta-Analysis (Novak et al 2016)
In 2016 Novak et al performed and systematic review and meta-analysis to assess safety and efficacy of stem cell therapy in patients with cerebral palsy (CP). Five clinical trials involving 328 patients were included. Cell types, cell dose and delivery route were not uniform. Four cell types were studied including olfactory ensheathing, neural, neural progenitors, and allogeneic umbilical cord blood (UCBs). Delivery routes included intrathecal injection, neurosurgical implantation, and intravenous and intrarterial infusion. Stem cell therapy was safe, and well tolerated with similar adverse events between treatment and control groups and low rates of serious adverse events among trials. All five trials reported benefits from stem cell therapy on gross motor function as measured by Gross Motor Function Measurement scale (GMFM). The two studies that used umbilical cord blood (UCB), found that UCB with or without rehabilitation had a greater impact on gross motor function than rehabilitation alone. Novak et al concluded that “our meta-analysis demonstrated that stem cell intervention for people with cerebral palsy have a small but significant short-term impact on gross motor skills” and “has a larger treatment effect than rehabilitation alone.”
Human allogeneic AB0/Rh-identical umbilical cord blood cells in the treatment of juvenile patients with cerebral palsy (Romanov et al 2015)
In 2015 Romanov et al performed a post-registration clinical study to evaluate the safety and efficacy of repeated intravenous infusions of allogeneic umbilical cord blood (UCB) in children aged 1-12 years old with cerebral palsy (CP). Severe forms of CP were prevalent in this study with 50% of patients being tetraplegic. Patients received up to 6 intravenous infusions and were followed for 3-36 months. Infusion with UCB was well tolerated, and no acute or delayed adverse reactions were observed. Efficacy was evaluated using standardized measurement tools to measure muscle tone, physical development, neurological status, mental status and gross motor function. Positive changes in muscle tone, physical development, neurological status and mental development were observed more in the group of patients aged 2-6 years old. Positive changes in neurological status were predominately observed in the group of patients older than 6 years old. After analysis between effectiveness of treatment and other factors such as symptom severity and number of treatments, Romanov et al found that patient’s age is not the main predictor of success. Overall improvements in neurological, physical activity and/or intellectual development were seen in approximately 70% patients. No negative trends were observed in any of the children who received treatment. The best results were achieved in children who received five or more infusions. Improvements in neurological and physical status in 85.7% of patients and improvement in mental status in 100% of patients were observed. Romanov et al concluded that “These findings indicate that repeated intravenous infusions of allogeneic HLA-unmatched ABO/Rh- identical UCB cells to pediatric patients with CP is safe and is an effective intervention in most cases.”
Involvement of Immune Responses in the Efficacy of Cord Blood Cell Therapy for Cerebral Palsy (Kang et al 2015)
In 2015 Kang et al conducted a randomized, placebo controlled, double blind trial to assess the efficacy of intravenous or intra-arterial infusions of umbilical cord blood (UCB) in 17 patients aged 6 months to 20 years old with cerebral palsy (CP). 15 of 17 patients received intravenous infusion. No serious adverse events occurred during the study. Gross Motor Function Measure (GMFM) and Gross Motor Performance Measure (GMPM) were used to assess gross motor control. Other measurement tools including the Bayley Scales of Infant Development-II, Functional Independence Measure for Children (WeeFIM) and the Pediatric Evaluation of Disability Inventory (PEDI) were also used to assess functional changes. Immune markers including PTX3, a prognostic marker in inflammatory syndromes and brain injury, and anti-inflammatory cytokines including IL-8 and Il-10, were evaluated and analyzed. F-FDG PET scan to assess change in glucose metabolism and brain activity was also evaluated. Patients treated with UCB showed significant greater improvements in muscle strength measured by manual muscle testing and gross motor performance as measured by GMPM scores when compared to baseline. Increased PTX3 and IL-8 levels were closely correlated with improvements in motor function in patients who received UCB infusion. Plasma levels of PTX3 had the highest correlation with clinical outcomes. F-FDG PET scans after UCB infusion showed anti-inflammatory effects in numerous areas of the brain commonly affected in periventricular leukomalacia, the most frequent cause of CP. F-FDG PET scans also showed increased metabolism in motor regions of the brain after UCB infusion and indicate an activation of motor function. Kang et al concluded that “treatment with allogeneic UCB alone improved motor outcomes in children with CP and proved to be therapeutically effective.”
Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: A double-blind, randomized, placebo-controlled trial (Min et al 2013)
In 2013 Min et al conducted a double-blind, randomized, placebo-controlled trial to assess the efficacy of a single intravenous umbilical cord blood infusion with erythropoietin (EPO) injections in children with cerebral palsy (CP). Patients diagnosed with CP between the ages of 10 months and 10 years of age were included in the study and randomized into three groups all of which participated in rehabilitation. The “pUCB Group” received UCB with EPO, the “EPO Group” received EPO with placebo UCB and the “Control Group” received placebo UCB and placebo EPO. The Gross Motor Function Measure (GMFM) and Gross Motor Performance Measure (GMPM) were used to measure gross motor ability, and the BSID-II was used to measure neurodevelopmental progress. F-FDG PET scans and brain MRI were used to detect metabolic and structural changes, respectively, in the brain before and after treatment. The “pUCB Group” showed greater significant motor function improvements compared to both other groups as measured by significant higher scores of GMPM and BSID-II Motor scale. Cognitive outcomes were higher in the “pUCB group” compared to other groups as measured by improvements in BSID-II Mental scales and WeeFIM score. F-FDG PET scans showed different areas of increased and decreased metabolic activity among the three groups. Brain MRI using diffusion tensor imaging (DTI) to measure fractional anisotropy (FA), a measure of white matter integrity, and the structural integrity of the corticospinal tract showed improved structural changes only in the “pUCB Group.” Increased FA was correlated with increased GMPM score. Ten serious adverse events that required hospitalization were reported and incidence did not differ between groups. Pneuomnia and irritability were the most frequent non-serious adverse events in the “pUCB Group.” There were no prolonged or delayed serious adverse events reported at 1 year follow up. Min et al concluded that “In conclusion, UCB treatment ameliorated motor and cognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural and metabolic changes in the brain”
Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy. (Lee et al 2012)/p>
In 2012 Lee et al conducted a pilot study to assess the safety and feasibility of a single intravenous infusion of autologous cord blood mononuclear cells (CBMNCs) in children, 2-10 years of age with cerebral palsy (CP). Safety was assessed by monitoring vitals, symptoms related to toxicity, neurodevelopment tests and frequency of adverse events. Infusion was generally well-tolerated with minimal adverse events which were controlled with medication and intravenous hydration. Potential efficacy was measured by brain MRI to measure Fractional Anisotropy (FA) to assess structural changes and SPECT scan to assess changes in brain perfusion. Various standardized assessment tools to measure developmental, motor and cognitive functions were also used. Results showed that 25% of children had partial improvements in neurodevelopment evaluations tests after a single intravenous infusion of CBMNCs. The neurodevelopment improvements were significant in patients with hemiplegia or diplegia compared to quadriplegia. Brain MRI found significant differences in FA values after infusion with CBMNCs in only 3 regions of interest. Most patients did not show significant changes in brain perfusion based on SPECT images. Only 10% of patients demonstrated improved perfusion. Lee et al concluded that “Autologous intravenous CBMNC infusion seems to be practical and safe and has yielded potential benefits in children with CP.”
SOURCES OF SELECTED STUDIES:
- Huang, L., Zhang, C., Gu, J., Wu, W., Shen, Z., Zhou, X., & Lu, H. (2018). A Randomized, Placebo-Controlled Trial of Human Umbilical Cord Blood Mesenchymal Stem Cell Infusion for Children With Cerebral Palsy. Cell Transplantation, 27(2), 325–334. https://doi.org/10.1177/0963689717729379
- Sun, J. M., Song, A. W., Case, L. E., Mikati, M. A., Gustafson, K. E., Simmons, R., … Kurtzberg, J. (2017). Effect of Autologous Cord Blood Infusion on Motor Function and Brain Connectivity in Young Children with Cerebral Palsy: A Randomized, Placebo-Controlled Trial. Stem Cells Translational Medicine, 6(12), 2071–2078. https://doi.org/10.1002/sctm.17-0102
- Novak, I., Walker, K., Hunt, R. W., Wallace, E. M., Fahey, M., & Badawi, N. (2016). Concise Review: Stem Cell Interventions for People With Cerebral Palsy: Systematic Review With Meta-Analysis. STEM CELLS Translational Medicine, 5(8), 1014–1025. https://doi.org/10.5966/sctm.2015-0372
- Romanov, Y. A., Tarakanov, O. P., Radaev, S. M., Dugina, T. N., Ryaskina, S. S., Darevskaya, A. N., … Smirnov, V. N. (2015). Human allogeneic AB0/Rh-identical umbilical cord blood cells in the treatment of juvenile patients with cerebral palsy. Cytotherapy, 17(7), 969–978. https://doi.org/10.1016/j.jcyt.2015.02.010
- Kang, M., Min, K., Jang, J., Kim, S. C., Kang, M. S., Jang, S. J., … Kim, M. (2015). Involvement of Immune Responses in the Efficacy of Cord Blood Cell Therapy for Cerebral Palsy. Stem Cells and Development, 24(19), 2259–2268. https://doi.org/10.1089/scd.2015.0074
- Min, K., Song, J., Kang, J. Y., Ko, J., Ryu, J. S., Kang, M. S., … Kim, M. (2013). Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: A double-blind, randomized, placebo-controlled trial. Stem Cells, 31(3), 581–591. https://doi.org/10.1002/stem.1304
- Lee, Y.-H., Choi, K. V., Moon, J. H., Jun, H.-J., Kang, H.-R., Oh, S.-I., … Yang, Y.-S. (2012). Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy. Journal of Translational Medicine, 10, 58. https://doi.org/10.1186/1479-5876-10-58
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