Therapeutic evidence of umbilical cord-derived mesenchymal stem cell transplantation for cerebral palsy: a randomized, controlled trial
Tóm tắt
Cerebral palsy (CP) is a syndrome of childhood movement and posture disorders. Clinical evidence is still limited and sometimes inconclusive about the benefits of human umbilical cord mesenchymal stem cells (hUC-MSCs) for CP. We conducted a randomized trial to evaluate the safety and efficacy of hUC-MSC transplantation concomitant with rehabilitation in patients with CP. Eligible patients were allocated into the hUC-MSC group and control group. In addition to rehabilitation, the patients in the hUC-MSC group received four transfusions of hUC-MSCs intravenously, while the control group received a placebo. Adverse events (AEs) were collected for safety evaluation in the 12-month follow-up phase. Primary endpoints were assessed as activities of daily living (ADL), comprehensive function assessment (CFA), and gross motor function measure (GMFM) scales. In addition, cerebral metabolic activity was detected by 18F-FDG-PET/CT to explore the possible mechanism of the therapeutic effects. Primary endpoint data were analyzed by ANOVA using SPSS version 20.0. Forty patients were enrolled, and 1 patient withdrew informed consent. Therefore, 39 patients received treatments and completed the scheduled assessments. No significant difference was shown between the 2 groups in AE incidence. Additionally, significant improvements in ADL, CFA, and GMFM were observed in the hUC-MSC group compared with the control group. In addition, the standard uptake value of 18F-FDG was markedly increased in 3 out of 5 patients from the hUC-MSC group at 12 months after transplantation. Our clinical data showed that hUC-MSC transplantation was safe and effective at improving the gross motor and comprehensive function of children with CP when combined with rehabilitation. Recovery of cerebral metabolic activity might play an essential role in the improvements in brain function in patients with CP. The therapeutic window, transfusion route, and dosage in our study were considerable for reference in clinical application. Chictr.org.cn,
ChiCTR1800016554
. Registered 08 June 2018—retrospectively registered. The public title was “Randomized trial of umbilical cord-derived mesenchymal stem cells for cerebral palsy.”
Tài liệu tham khảo
Colver A, Fairhurst C, Pharoah PO. Cerebral palsy. Lancet. 2014;383(9924):1240–9.
Richards CL, Malouin F. Cerebral palsy: definition, assessment and rehabilitation. Handb Clin Neurol. 2013;111:183–95.
Graham HK, Rosenbaum P, Paneth N et al. Cerebral palsy. Nat Rev Dis Primers.2016;2016:15082. https://doi.org/10.1038/nrdp.2015.82.
Oskoui M, Coutinho F, Dykeman J, Jetté N, Pringsheim T. An update on the prevalence of cerebral palsy: a systematic review and meta-analysis. Dev Med Child Neurol. 2013;55(6):509–19.
Dambi JM, Jelsma J, Mlambo T, et al. An evaluation of psychometric properties of caregiver burden outcome measures used in caregivers of children with cerebral palsy: a systematic review protocol. Syst Rev. 2016;5:42–7.
McAdams RM, Juul SE. Cerebral palsy: prevalence, predictability, and parental counseling. Neoreviews. 2011;12(10):564–74.
MacLennan AH, Thompson SC, Gecz J. Cerebral palsy: causes, pathways, and the role of genetic variants. Am J Obstet Gynecol. 2015;213(6):779–88.
Kułak P, Maciorkowska E, Gościk E. Volumetric Magnetic Resonance Imaging Study of Brain and Cerebellum in Children with Cerebral Palsy. Biomed Res Int.2016;2016:5961928. https://doi.org/10.1155/2016/5961928
HC F. Current proceedings of cerebral palsy. Cell Transplant. 2015;24:471–85.
Kiasatdolatabadi A, Lotfibakhshaiesh N, Yazdankhah M, et al. The role of stem cells in the treatment of cerebral palsy: a review. Mol Neurobiol. 2017;54(7):4963–72.
Novak I, Walker K, Hunt RW, et al. Concise review: stem cell interventions for people with cerebral palsy: systematic review with meta-analysis. Stem Cells Transl Med. 2016;5(8):1014–25.
Ruff CA, Faulkner SD, Fehlings MG. The potential for stem cell therapies to have an impact on cerebral palsy: opportunities and limitations. Dev Med Child Neurol. 2013;55(8):689–97.
Morioka C, Komaki M, Taki A, et al. Neuroprotective effects of human umbilical cord-derived mesenchymal stem cells on periventricular leukomalacia-like brain injury in neonatal rats. Inflamm Regen. 2017;37:1.
Zhou X, Gu J, Gu Y, et al. Human umbilical cord-derived mesenchymal stem cells improve learning and memory function in hypoxic-ischemic brain-damaged rats via an IL-8-mediated secretion mechanism rather than differentiation pattern induction. Cell Physiol Biochem. 2015;35(6):2383–401.
Zhang X, Zhang Q, Li W, et al. Therapeutic effect of human umbilical cord mesenchymal stem cells on neonatal rat hypoxic-ischemic encephalopathy. J Neurosci Res. 2014;92(1):35–45.
Okur SÇ, Erdoğan S, Demir CS, Günel G, Karaöz E. The effect of umbilical cord-derived mesenchymal stem cell transplantation in a patient with cerebral palsy: a case report. Int J Stem Cells. 2018;11(1):141–7.
Abi Chahine NH, Wehbe TW, Hilal RA, et al. Treatment of cerebral palsy with stem cells: a report of 17 cases. Int J Stem Cells. 2016;9(1):90–5.
Shroff G, Gupta A, Barthakur JK. Therapeutic potential of human embryonic stem cell transplantation in patients with cerebral palsy. J Transl Med. 2014;12:318–26.
Mlinac ME, Feng MC. Assessment of activities of daily living, self-care, and independence. Arch Clin Neuropsychol. 2016;31(6):506–16.
Hu YY, Wu WH, Li YC, et al. Research on comprehensive function assessment for disabled children: part I design. Chin J Rehabil Theory Practice. 2001;7(3):108–12.
Ko J, Kim M. Reliability and responsiveness of the gross motor function measure-88 in children with cerebral palsy. Phys Ther. 2013;93(3):393–400.
Jones MW, Morgan E, Shelton JE, Thorogood C. Cerebral palsy introduction and diagnosis (part I). J Pediatr Health Care. 2007;21(3):146–52.
Rosenbaum P, Paneth N, Leviton A, et al. A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl. 2007;109:8–14.
Szczepiorkowski Z, Nunes E. AABB cell therapy standards. Cell Ther. 2009;2009:87–95.
Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. Int Soc Cell Ther Position Statement. 2006;8(4):315–7.
Bobath B. The very early treatment of cerebral palsy. Dev Med Child Neurol. 1967;9(4):373–90.
Shepherd R. The bobath concept in the treatment of cerebral palsy. Aust J Physiother. 1968;14(3):79–85.
Robinson RO, McCarthy GT, Little TM. Conductive education at the Petö Institute, Budapest. BMJ. 1989;299(6708):1145–9.
Lameka K, Farwell MD, Ichise M. Positron emission tomography. Handb Clin Neurol. 2016;135:209–27.
Wang L, Ji H, Zhou J, et al. Therapeutic potential of umbilical cord mesenchymal stromal cells transplantation for cerebral palsy: a case report. Case Rep Transplant. 2013;3:15–8.
Dong H, Li G, Shang C, et al. Umbilical cord mesenchymal stem cell (UC-MSC) transplantations for cerebral palsy. Am J Transl Res. 2018;10(3):901–6.
Wang X, Hu H, Hua R, et al. Effect of umbilical cord mesenchymal stromal cells on motor functions of identical twins with cerebral palsy pilot study on the correlation of efficacy and hereditary factors. Cytotherapy. 2015;17(2):224–31.
Zhang C, Huang L, Gu J, Zhou X. Therapy for Cerebral Palsy by Human Umbilical Cord Blood Mesenchymal Stem Cells Transplantation Combined With Basic Rehabilitation Treatment: A Case Report. Glob Pediatr Health.2015;2:2333794X15574091. https://doi.org/10.1177/2333794X15574091.
Huang L, Zhang C, Gu J, et al. A randomized, placebo-controlled trial of human umbilical cord blood mesenchymal stem cell infusion for children with cerebral palsy. Cell Transplant. 2018;27(2):325–34.
Min K, Song J, Kang JY, et al. Umbilical cord blood therapy potentiated with erythropoietin for children with cerebral palsy: a double-blind, randomized, placebo-controlled trial. Stem Cells. 2013;31(3):581–91.
Feng M, Lu A, Gao H, et al. Safety of allogeneic umbilical cord blood stem cells therapy in patients with severe cerebral palsy: a retrospective study. Stem Cells Int. 2015;2:214–20.
Cho PS, Messina DJ, Hirsh EL, Chi N, Goldman SN. Immunogenicity of umbilical cord tissue derived cells. Blood. 2008;111(1):430–8.
De Miguel MP, Fuentes-Julián S, Blázquez-Martínez A, Pascual CY, Aller MA. Immunosuppressive properties of mesenchymal stem cells. Curr Mol Med.2012;12(5):574–91.
Gao L, Zhang Y, Hu B, et al. Phase II multicenter, randomized, double-blind controlled study of efficacy and safety of umbilical cord-derived mesenchymal stromal cells in the prophylaxis of chronic graft-versus-host disease after HLA-haploidentical stem-cell transplantation. J Clin Oncol. 2016;34(24):2843–50.
Wang D, Niu L, Feng X, et al. Long-term safety of umbilical cord mesenchymal stem cells transplantation for systemic lupus erythematosus: a 6-year follow-up study. Clin Exp Med. 2017;17(3):333–40.
Park YB, Ha CW, Lee CH, Yoon YC, Park YG. Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof of concept with 7 years of extended follow-up. Stem Cells Transl Med. 2017;6(2):613–21.
Bae SH, Kong TH, Lee HS, et al. Long-lasting paracrine effects of human cord blood cells on damaged neocortex in an animal model of cerebral palsy. Cell Transplant. 2012;21(11):2497–515.
Cotten CM, Murtha AP, Goldberg RN, et al. Feasibility of autologous cord blood cells for infants with hypoxic-ischemic encephalopathy. J Pediatr. 2014;164(5):973–9.
Saquetto M, Carvalho V, Silva C, Conceição C, Gomes-Neto M. The effects of whole body vibration on mobility and balance in children with cerebral palsy a systematic review with meta-analysis. J Musculoskelet Neuronal Interact. 2015;15(2):137–44.
Fleiss B, Gressens P. Tertiary mechanisms of brain damage: a new hope for treatment of cerebral palsy. Lancet Neurol. 2012;11(6):556–66.
Bae SH, Lee HS, Kang MS, et al. The levels of pro-inflammatory factors are significantly decreased in cerebral palsy patients following an allogeneic umbilical cord blood cell transplant. Int J Stem Cells. 2012;5(1):31–8.
Huang H, Young W, Chen L, et al. Clinical cell therapy guidelines for neurorestoration (IANRCANR 2017). Cell Transplant. 2018;27(2):310–24.
Thorngren-Jerneck K, Ohlsson T, Sandell A, et al. Cerebral glucose metabolism measured by positron emission tomography in term newborn infants with hypoxic ischemic encephalopathy. Pediatr Res. 2001;49(4):495–501.
Kang M, Min K, Jang J, et al. Involvement of immune responses in the efficacy of cord blood cell therapy for cerebral palsy. Stem Cells Dev. 2015;24(19):2259–68.