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Neuroregenerative potential of intravenous G-CSF and autologous peripheral blood stem cells in children with cerebral palsy: a randomized, double-blind, cross-over study.

ABSTRACT: We performed a randomized, double-blind, cross-over study to assess the neuroregenerative potential of intravenous granulocyte colony-stimulating factor (G-CSF) followed by infusion of mobilized peripheral blood mononuclear cells (mPBMCs) in children with cerebral palsy (CP).Children with non-severe CP were enrolled in this study. G-CSF was administered for 5 days, then mPBMCs were collected by apheresis and cryopreserved. One month later (M1), recipients were randomized to receive either mPBMCs or a placebo infusion, and these treatment groups were switched at 7 months (M7) and observed for another 6 months (M13). We assessed the efficacy of treatment by evaluating neurodevelopmental tests, as well as by brain magnetic resonance imaging-diffusion tensor imaging (MRI-DTI) and 18F-fluorodeoxyglucose (FDG) brain positron emission tomography-computed tomography (PET-CT) scanning to evaluate the anatomical and functional changes in the brain.Fifty-seven patients aged 4.3 ± 1.9 (range 2-10) years and weighing 16.6 ± 4.9 (range 11.6-56.0) kg were enrolled in this study. The administration of G-CSF as well as the collection and reinfusion of mPBMCs were safe and tolerable. The yield of mPBMCs was comparable to that reported in studies of pediatric donors without CP and patients with nonhematologic diseases. 42.6% of the patients responded to the treatment with higher neurodevelopmental scores than would normally be expected. In addition, larger changes in neurodevelopment test scores were observed in the 1 month after G-CSF administration (M0-M1) than during the 6 months after reinfusion with mPBMCs or placebo (M1-M7 or M7-M13). Patients who received G-CSF followed by mPBMC infusion at 7 months (T7 group) demonstrated significantly more neurodevelopmental improvement than patients who received G-CSF followed by mPBMC infusion at 1 month (T1 group). In contrast to the results of neurodevelopment tests, the results of MRI-DTI at the end of this study showed greater improvement in the T1 group. Although we observed metabolic changes to the cerebellum, thalamus and cerebral cortex in the 18F-FDG brain PET-CT scans, there were no significant differences in such changes between the mPBMC and placebo group or between the T1 and T7 group.Neurodevelopmental improvement was seen in response to intravenous G-CSF followed by mPBMC reinfusion, particularly to the G-CSF alone even without mPBMC reinfusion. Further studies using a larger number of mPBMCs for the infusion which could be collected by repeated cycles of apheresis or using repeated cycles of G-CSF alone, are needed to clarify the effect of mPBMC reinfusion or G-CSF alone (Trial registration: ClinicalTrials.gov, NCT02983708. Registered 5 December, 2016, retrospectively registered).

SUBMITTER: Rah WJ

PROVIDER: S-EPMC5251252 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Neuroregenerative potential of intravenous G-CSF and autologous peripheral blood stem cells in children with cerebral palsy: a randomized, double-blind, cross-over study.

Rah Wee-Jin WJ Lee Young-Ho YH Moon Jin-Hwa JH Jun Hyun-Ju HJ Kang Hye-Ryeong HR Koh Hani H Eom Hye Jung HJ Lee Ji Young JY Lee Young Jun YJ Kim Ji Young JY Choi Yun-Young YY Park Kyeongil K Kim Mi Jung MJ Kim Seung-Hyun SH

Journal of translational medicine 20170121 1

<h4>Objective</h4>We performed a randomized, double-blind, cross-over study to assess the neuroregenerative potential of intravenous granulocyte colony-stimulating factor (G-CSF) followed by infusion of mobilized peripheral blood mononuclear cells (mPBMCs) in children with cerebral palsy (CP).<h4>Methods</h4>Children with non-severe CP were enrolled in this study. G-CSF was administered for 5 days, then mPBMCs were collected by apheresis and cryopreserved. One month later (M1), recipients were r ...[more]

PMID: 28109298

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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.

Project description:Chronic non-specific low back pain is a major socioeconomic public health issue worldwide and, despite the volume of research in the area, it is still a difficult-to-treat condition. The conservative analgesic therapy usually comprises a variety of pharmacological and non-pharmacological strategies, such as transcutaneous electrical nerve stimulation. The neuromatrix pain model and the new findings on the process of chronicity of pain point to a higher effectiveness of treatments that address central rather than peripheral structures. The transcranial direct current stimulation is a noninvasive technique of neuromodulation that has made recent advances in the treatment of chronic pain. The simultaneous combination of these two electrostimulation techniques (cerebral and peripheral) can provide an analgesic effect superior to isolated interventions. However, all the evidence on the analgesic efficacy of these techniques, alone or combined, is still fragmented. This is a protocol for a randomized clinical trial to investigate whether cerebral electrical stimulation combined with peripheral electrical stimulation is more effective in relieving pain than the isolated application of electrical stimulations in patients with chronic nonspecific low back pain.Ninety-two patients will be randomized into four groups to receive transcranial direct current stimulation (real/sham)?+ transcutaneous electrical nerve stimulation (real/sham) for 12 sessions over a period of four weeks. The primary clinical outcome (pain intensity) and the secondary ones (sensory and affective aspects of pain, physical functioning and global perceived effect) will be recorded before treatment, after four weeks, in Month 3 and in Month 6 after randomization. Confounding factors such as anxiety and depression, the patient's satisfaction with treatment and adverse effects will also be listed. Data will be collected by an examiner unaware of (blind to) the treatment allocation.The results of this study may assist in clinical decision-making about the combined use of cerebral and peripheral electrical stimulation for pain relief in patients with chronic low back pain.NCT01896453.

Dataset Information

Neuroregenerative potential of intravenous G-CSF and autologous peripheral blood stem cells in children with cerebral palsy: a randomized, double-blind, cross-over study.

Publications

Neuroregenerative potential of intravenous G-CSF and autologous peripheral blood stem cells in children with cerebral palsy: a randomized, double-blind, cross-over study.

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