Safety and Efficacy of Allogeneic Umbilical Cord Blood Therapy for Global Development Delay and Intellectual Disability.

Most pediatric patients with global developmental delay (GDD) or intellectual disability (ID) have disrupted development. Since allogeneic umbilical cord blood (UCB) may exert neurotrophic effects, a prospective clinical trial was conducted to assess the efficacy and safety of UCB therapy for GDD and ID. A total of 13 children (ages 23-149 months) with GDD and ID were enrolled and followed up for 12 months. Under criteria of histocompatibility and cell number, allogeneic UCB units were selected and infused once intravenously, and adverse events were monitored. The Bayley Scale of Infant Development-II (BSID-II) was used as primary outcome measurement tool, and evaluations for various functional abilities were also implemented. Safety assessment did not reveal significant adverse effects. Functional improvements in mental and motor developments along with daily living activities and languages were observed at 12 months postintervention compared with the baseline abilities (P < 0.05). Furthermore, mental developmental quotient derived from BSID-II mental scale revealed significantly facilitated improvement during the first 3 months (P < 0.05). In the survey conducted 80.7 ± 13.0 months after UCB infusion to assess satisfaction and long-term safety, no long-term adverse effects were reported, and 70% of the guardians reported satisfaction with the UCB infusion. Long-term changes in two patients who were regularly followed up beyond the study completion were noticeable. One case observed for 4 years showed dramatic improvement until 12 months after UCB therapy, whereas she showed insignificant improvement beyond 12 months after the therapy. Another case showed alleviation of autism with findings of anti-inflammatory response in his peripheral blood after UCB infusion. This clinical study provides support for further applications of UCB as a therapeutic avenue for children with GDD or ID owing to its safety and partial efficacy. Due to patient heterogeneity, further studies focusing on specific clinical manifestations and etiologies are required. Registered at www.clinicaltrials.gov (NCT01769716).

Efficacy of Cord Blood Cell Therapy for Hutchinson-Gilford Progeria Syndrome-A Case Report.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare premature aging disorder characterized by short stature and atherosclerosis-induced death within teenage years. A 13-year-old male diagnosed with HGPS was administered three intravenous infusions of allogeneic cord blood (CB) cells from unrelated donors at four-month intervals to evaluate the safety and its therapeutic efficacy. Adverse events were monitored in addition to height, weight, laboratory blood tests, joint range of motion (ROM), and carotid Doppler. Cytokine and receptor assays were also performed. The patient exhibited an increase in growth rate for both height and weight. One year after therapy initiation, evident amelioration in pulse wave velocity, bilateral maximal intima-media thickness, and dyslipidemic status were observed, which were in abrupt aggravation prior to treatment. Further, an increase in flexibility occurred in some joints of the upper extremities. No serious adverse events were observed throughout the study period and one year beyond. A molecular assay revealed downregulation of proinflammatory and atherosclerosis, representing cytokine expressions following the administration of CB cells. This is the first reported case of an allogeneic CB trial in a patient with HGPS showing therapeutic effects of CB with improvements in anthropometric measures, joint ROM with amelioration of atherosclerosis, and dyslipidemia induced by anti-inflammatory and anti-atherosclerotic responses.

Synergistic Effect in Neurological Recovery via Anti-Apoptotic Akt Signaling in Umbilical Cord Blood and Erythropoietin Combination Therapy for Neonatal Hypoxic-Ischemic Brain Injury.

Our previous clinical studies demonstrated the synergistic therapeutic effect induced by co-administering recombinant human erythropoietin (rhEPO) in human umbilical cord blood (hUCB) therapy for children with cerebral palsy. However, the cellular mechanism beyond the beneficial effects in this combination therapy still needs to be elucidated. A hypoxic-ischemic encephalopathy (HIE) model of neonates, representing cerebral palsy, was prepared and randomly divided into five groups (hUCB+rhEPO combination, hUCB, and rhEPO treatments over HIE, HIE control, and sham). Seven days after, hUCB was administered intraperitoneally and the rhEPO injections were started. Neurobehavioral tests showed the best outcome in the combination therapy group, while the hUCB and rhEPO alone treatments also showed better outcomes compared with the control (p < 0.05). Inflammatory cytokines were downregulated by the treatments and attenuated most by the combination therapy (p < 0.05). The hUCB+rhEPO treatment also showed remarkable increase in phosphorylation of Akt and potentiation of anti-apoptotic responses with decreased Bax and increased Bcl-2 (p < 0.05). Pre-treatment of MK-2206, an Akt inhibitor, for the combination therapy depressed the anti-apoptotic effects. In conclusion, these findings suggest that the therapeutic effect of hUCB therapy might be potentiated by co-administration of rhEPO via augmentation of anti-inflammatory and anti-apoptotic responses related to the phosphorylation of Akt.

Potentiation of cord blood cell therapy with erythropoietin for children with CP: a 2 × 2 factorial randomized placebo-controlled trial.

BACKGROUND: Concomitant administration of allogeneic umbilical cord blood (UCB) infusion and erythropoietin (EPO) showed therapeutic efficacy in children with cerebral palsy (CP). However, no clinical studies have investigated the effects of UCB and EPO combination therapy using a 2 × 2 four-arm factorial blinded design with four arms. This randomized placebo-controlled trial aimed to identify the synergistic and individual efficacies of UCB cell and EPO for the treatment of CP. METHODS: Children diagnosed with CP were randomly segregated into four groups: (A) UCB+EPO, (B) UCB+placebo EPO, (C) placebo UCB+EPO, and (D) placebo UCB+placebo EPO. Based on the UCB unit selection criteria of matching for ≥ 4/6 of human leukocyte antigen (HLA)-A, -B, and DRB1 and total nucleated cell (TNC) number of ≥ 3 × 107/kg, allogeneic UCB was intravenously infused and 500 IU/kg human recombinant EPO was administered six times. Functional measurements, brain imaging studies, and electroencephalography were performed from baseline until 12 months post-treatment. Furthermore, adverse events were closely monitored. RESULTS: Eighty-eight of 92 children enrolled (3.05 ± 1.22 years) completed the study. Change in gross motor performance measure (GMPM) was greater in group A than in group D at 1 month (△2.30 vs. △0.71, P = 0.025) and 12 months (△6.85 vs. △2.34, P = 0.018) post-treatment. GMPM change ratios were calculated to adjust motor function at the baseline. Group A showed a larger improvement in the GMPM change ratio at 1 month and 12 months post-treatment than group D. At 12 months post-treatment, the GMPM change ratios were in the order of groups A, B, C, and D. These results indicate synergistic effect of UCB and EPO combination better than each single therapy. In diffusion tensor imaging, the change ratio of fractional anisotropy at spinothalamic radiation was higher in group A than group D in subgroup of age ≥ 3 years. Additionally, higher TNC and more HLA-matched UCB units led to better gross motor outcomes in group A. Adverse events remained unchanged upon UCB or EPO administration. CONCLUSIONS: These results indicate that the efficacy of allogeneic UCB cell could be potentiated by EPO for neurological recovery in children with CP without harmful effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01991145 , registered 25 November 2013.

Remarkable improvement in a very severe chronic obstructive pulmonary disorder patient after use of noninvasive intermittent positive pressure ventilator: A case report.

RATIONAL: Chronic obstructive pulmonary disease (COPD) impairs lung function and induces systemic effects, resulting in impaired quality of life. Skeletal muscle dysfunction-characteristic of advanced COPD patients-limits a patient's ability to perform activities of daily living (ADL). In addition, dysphagia is commonly observed in COPD patients. PATIENT CONCERN: This case report documents a 42-year-old man with very severe COPD. He experienced aggravation of the symptoms during standard medical treatment and his ability to perform the ADL was significantly impaired. Furthermore, his dysphagia worsened despite oromotor training. DIAGNOSIS: He was diagnosed as very severe COPD have a problem with swallowing and respiratory function. INTERVENTION: Upon NIPPV treatment, the patient's ability to perform the ADL, as well as his dysphagia, showed improvement. OUTCOMES: Thus, we report the remarkable improvement of physical function, as well as dysphagia, in a very severe COPD patient after NIPPV treatment. LESSONS: NIPPV may be useful as a treatment option for such patients.

Multiplex Ligation-Dependent Probe Amplification in X-linked Recessive Muscular Dystrophy in Korean Subjects.

PURPOSE: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are similar genetic disorders whose patterns of mutation and disease phenotypes might be expected to show differences among different countries. We analyzed multiplex ligation-dependent probe amplification (MLPA) data in a large number of Korean patients with DMD/BMD. MATERIALS AND METHODS: We obtained 130 positive MLPA results (86 DMD, 27 BMD, and 17 female carriers) from 272 candidates (237 clinically suspected patients and 35 possible female carriers) who took part in this study. We analyzed the mutation patterns among 113 patients diagnosed by MLPA and calculated deletion/duplication percentages from a total of 128 patients, including 15 patients who were diagnosed using methods other than MLPA. We also analyzed hot spot locations among the 130 MLPA-positive results. RESULTS: Most mutations were detected in a central hot spot region between exons 44 and 55 (80 samples, 60.6%). Unlike previous reports, a second frequently observed hot spot near the 5'-end was not distinctive. MLPA detected deletions in specific exons in 92 patients with DMD/BMD (71.8%) and duplications in 21 patients (16.4%). CONCLUSION: Our MLPA study of a large number of Korean patients with DMD/BMD identified the most frequent mutation hot spot, as well as a unique hot spot pattern. DMD gene mutation patterns do not appear to show significant ethnic differences.