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First autologous cell therapy of cerebral palsy caused by hypoxic-ischemic brain damage in a child after cardiac arrest-individual treatment with cord blood.

ABSTRACT: Each year, thousands of children incur brain damage that results in lifelong sequelae. Therefore, based on experimental evidence, we explored the therapeutic potential of human cord blood, known to contain stem cells, to examine the functional neuroregeneration in a child with cerebral palsy after cardiac arrest. The boy, whose cord blood was stored at birth, was 2.5 years old and normally developed when global ischemic brain damage occurred resulting in a persistent vegetative state. Nine weeks later, he received autologous cord blood (91.7?mL, cryopreserved, 5.75 × 10e8 mononuclear cells) intravenously. Active rehabilitation (physio- and ergotherapy) was provided daily, follow-up at 2, 5, 12, 24, 30, and 40 months. At 2-months follow-up the boy's motor control improved, spastic paresis was largely reduced, and eyesight was recovered, as did the electroencephalogram. He smiled when played with, was able to sit and to speak simple words. At 40 months, independent eating, walking in gait trainer, crawling, and moving from prone position to free sitting were possible, and there was significantly improved receptive and expressive speech competence (four-word sentences, 200 words). This remarkable functional neuroregeneration is difficult to explain by intense active rehabilitation alone and suggests that autologous cord blood transplantation may be an additional and causative treatment of pediatric cerebral palsy after brain damage.

SUBMITTER: Jensen A

PROVIDER: S-EPMC3671311 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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First autologous cell therapy of cerebral palsy caused by hypoxic-ischemic brain damage in a child after cardiac arrest-individual treatment with cord blood.

Jensen A A Hamelmann E E

Case reports in transplantation 20130515

Each year, thousands of children incur brain damage that results in lifelong sequelae. Therefore, based on experimental evidence, we explored the therapeutic potential of human cord blood, known to contain stem cells, to examine the functional neuroregeneration in a child with cerebral palsy after cardiac arrest. The boy, whose cord blood was stored at birth, was 2.5 years old and normally developed when global ischemic brain damage occurred resulting in a persistent vegetative state. Nine weeks ...[more]

PMID: 23762741

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Project description:Human umbilical cord mesenchymal stem cells (hUCMSC) have shown promising potential in ameliorating brain injury, but the mechanism is unclear. We explore the role of NogoA/NgR/Rho pathway in mediating hUCMSC to improve neurobehavioral status and alleviate brain injury in hypoxia/ischemia-induced CP (cerebral palsy) rat model in order to promote the clinical application of stem cell therapy in CP. The injury model of HT22 cells was established after 3 h hypoxia, and then co-cultured with hUCMSC. The rat model of CP was established by ligation of the left common carotid artery for 2.5 h. Subsequently, hUCMSC was administered via the tail vein once a week for a total of four times. The neurobehavioral status of CP rats was determined by behavioral experiment, and the pathological brain injury was determined by pathological staining method. The mRNA and protein expressions of NogoA, NgR, RhoA, Rac1, and CDC42 in brain tissues of rats in all groups and cell groups were detected by real-time quantitative polymerase chain reaction (RT-qPCR), Western blot, and immunofluorescence. The CP rats exhibited obvious motor function abnormalities and pathological damage. Compared with the control group, hUCMSC transplantation could significantly improve the neurobehavioral situation and attenuate brain pathological injury in CP rats. The relative expression of NogoA, NgR, RhoA mRNA, and protein in brain tissues of rats in the CP group was significantly higher than the rats in the sham and CP+hUCMSC group. The relative expression of Rac1, CDC42 mRNA, and protein in brain tissues of rats in the CP group was significantly lower than the rats in the sham and CP+hUCMSC group. The animal experiment results were consistent with the experimental trend of hypoxic injury of HT22 cells. This study confirmed that hUCMSC can efficiently improve neurobehavioral status and alleviate brain injury in hypoxia/ischemia-induced CP rat model and HT22 cell model through downregulating the NogoA/NgR/Rho pathway.

Project description:Cerebral palsy (CP) is the most common motor disability in childhood, with a worldwide prevalence of 1.5-4/1,000 live births. Hypoxic-ischemic encephalopathy (HIE) contributes to the burden of CP, but the long-term neuropathological findings of this association remain limited.Thirty-four term Macaca nemestrina macaques were included in this long-term neuropathological study: 9 control animals delivered by cesarean section and 25 animals with perinatal asphyxia delivered by cesarean section after 15-18 min of umbilical cord occlusion (UCO). UCO animals were randomized to saline (n = 11), therapeutic hypothermia (TH; n = 6), or TH + erythropoietin (Epo; n = 8). Epo was given on days 1, 2, 3, and 7. Animals had serial developmental assessments and underwent magnetic resonance imaging with diffusion tensor imaging at 9 months of age followed by necropsy. Histology and immunohistochemical (IHC) staining of brain and brainstem sections were performed.All UCO animals demonstrated and met the standard diagnostic criteria for human neonates with moderate-to-severe HIE. Four animals developed moderate-to-severe CP (3 UCO and 1 UCO + TH), 9 had mild CP (2 UCO, 3 UCO + TH, 3 UCO + TH + Epo, and 1 control), and 2 UCO animals died. None of the animals treated with TH + Epo died, had moderate-to-severe CP, or demonstrated signs of long-term neuropathological toxicity. Compared to animals grouped together as having no CP (no-CP; controls and mild CP only), animals with CP (moderate and severe) demonstrated decreased fractional anisotropy of multiple white-matter tracts including the corpus callosum and internal capsule, when using Tract-Based Spatial Statistics (TBSS). Animals with CP had decreased staining for cortical neurons and increased brainstem glial scarring compared to animals without CP. The cerebellar cell density of the internal granular layer and white matter was decreased in CP animals compared to that in control animals without CP.In this nonhuman primate HIE model, animals treated with TH + Epo had less brain pathology noted on TBSS and IHC staining, which supports the long-term safety of TH + Epo in the setting of HIE. Animals that developed CP showed white-matter changes noted on TBSS, subtle histopathological changes in both the white and gray matter, and brainstem injury that correlated with CP severity. This HIE model may lend itself to further study of the relationship between brainstem injury and CP.

Project description:We examined an autologous mononuclear-cell-therapy-based approach to treat cerebral palsy using autologous umbilical cord blood or bone-marrow-derived mononuclear cells. The primary objective was to determine if autologous cells are safe to administer in children with cerebral palsy. The secondary objectives were to determine if there was improvement in motor function of patients 12 months after infusion using the Gross Motor Function Measure and to evaluate impact of treatment on corticospinal tract microstructure as determined by radial diffusivity measurement. This Phase 1/2a trial was a randomized, blinded, placebo-controlled, crossover study in children aged 2-10 years of age with cerebral palsy enrolled between November 2013 and November 2016. Participants were randomized to 2:1 treatment:placebo. Treatment was either autologous bone-marrow-derived mononuclear cells or autologous umbilical cord blood. All participants who enrolled and completed their baseline visit planned to return for follow-up visits at 6 months, 12 months and 24 months after the baseline visit. At the 12-month post-treatment visit, participants who originally received the placebo received either bone-marrow-derived mononuclear cell or umbilical cord blood treatment. Twenty participants were included; 7 initially randomized to placebo, and 13 randomized to treatment. Five participants randomized to placebo received bone-marrow-derived mononuclear cells, and 2 received umbilical cord blood at the 12-month visit. None of the participants experienced adverse events related to the stem cell infusion. Cell infusion at the doses used in our study did not dramatically alter motor function. We observed concordant bilateral changes in radial diffusivity in 10 of 15 cases where each corticospinal tract could be reconstructed in each hemisphere. In 60% of these cases (6/10), concordant decreases in bilateral corticospinal tract radial diffusivity occurred post-treatment. In addition, 100% of unilateral corticospinal tract cases (3/3) exhibited decreased corticospinal tract radial diffusivity post-treatment. In our discordant cases (n = 5), directionality of changes in corticospinal tract radial diffusivity appeared to coincide with handedness. There was a significant improvement in corticospinal tract radial diffusivity that appears related to handedness. Connectivity strength increased in either or both pathways (corticio-striatal and thalamo-cortical) in each participant at 12 months post-treatment. These data suggest that both stem cell infusions are safe. There may be an improvement in myelination in some groups of patients that correlate with small improvements in the Gross Motor Function Measure scales. A larger autologous cord blood trial is impractical at current rates of blood banking. Either increased private banking or matched units would be required to perform a larger-scale trial.

Dataset Information

First autologous cell therapy of cerebral palsy caused by hypoxic-ischemic brain damage in a child after cardiac arrest-individual treatment with cord blood.

Publications

First autologous cell therapy of cerebral palsy caused by hypoxic-ischemic brain damage in a child after cardiac arrest-individual treatment with cord blood.

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