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Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety.

ABSTRACT: Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12-24, 36-48, and 60-72?hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.

SUBMITTER: Tsuji M

PROVIDER: S-EPMC7067794 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety.

Tsuji Masahiro M Sawada Mariko M Watabe Shinichi S Sano Hiroyuki H Kanai Masayo M Tanaka Emi E Ohnishi Satoshi S Sato Yoshiaki Y Sobajima Hisanori H Hamazaki Takashi T Mori Rintaro R Oka Akira A Ichiba Hiroyuki H Hayakawa Masahiro M Kusuda Satoshi S Tamura Masanori M Nabetani Makoto M Shintaku Haruo H

Scientific reports 20200312 1

Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the U ...[more]

PMID: 32165664

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Project description:BackgroundHypoxic ischaemic encephalopathy (HIE) in newborns can cause significant long-term neurological disability. The insult is a complex injury characterised by energy failure and disruption of cellular homeostasis, leading to mitochondrial damage. The importance of individual metabolic pathways, and their interaction in the disease process is not fully understood. The aim of this study was to describe and quantify the metabolomic profile of umbilical cord blood samples in a carefully defined population of full-term infants with HIE.Methods and findingsThe injury severity was defined using both the modified Sarnat score and continuous multichannel electroencephalogram. Using these classification systems, our population was divided into those with confirmed HIE (n = 31), asphyxiated infants without encephalopathy (n = 40) and matched controls (n = 71). All had umbilical cord blood drawn and biobanked at -80 °C within 3 hours of delivery. A combined direct injection and LC-MS/MS assay (AbsolutIDQ p180 kit, Biocrates Life Sciences AG, Innsbruck, Austria) was used for the metabolomic analyses of the samples. Targeted metabolomic analysis showed a significant alteration between study groups in 29 metabolites from 3 distinct classes (Amino Acids, Acylcarnitines, and Glycerophospholipids). 9 of these metabolites were only significantly altered between neonates with Hypoxic ischaemic encephalopathy and matched controls, while 14 were significantly altered in both study groups. Multivariate Discriminant Analysis models developed showed clear multifactorial metabolite associations with both asphyxia and HIE. A logistic regression model using 5 metabolites clearly delineates severity of asphyxia and classifies HIE infants with AUC = 0.92. These data describe wide-spread disruption to not only energy pathways, but also nitrogen and lipid metabolism in both asphyxia and HIE.ConclusionThis study shows that a multi-platform targeted approach to metabolomic analyses using accurately phenotyped and meticulously biobanked samples provides insight into the pathogenesis of perinatal asphyxia. It highlights the potential for metabolomic technology to develop a diagnostic test for HIE.

Project description:ImportanceNeonatal hypoxic-ischemic encephalopathy (HIE) remains a significant cause of neurologic disability. Identifying infants suitable for therapeutic hypothermia (TH) within a narrow therapeutic time is difficult. No single robust biochemical marker is available to clinicians.ObjectiveTo assess the ability of a panel of candidate microRNA (miRNA) to evaluate the development and severity of encephalopathy following perinatal asphyxia (PA).Design, setting, and participantsThis validation study included 2 cohorts. For the discovery cohort, full-term infants with PA were enrolled at birth to the Biomarkers in Hypoxic-Ischemic Encephalopathy (BiHiVE1) study (2009-2011) in Cork, Ireland. Encephalopathy grade was defined using early electroencephalogram and Sarnat score (n = 68). The BiHiVE1 cohort also enrolled healthy control infants (n = 22). For the validation cohort, the BiHiVE2 multicenter study (2013-2015), based in Cork, Ireland (7500 live births per annum), and Karolinska Huddinge, Sweden (4400 live births per annum), recruited infants with PA along with healthy control infants to validate findings from BiHiVE1 using identical recruitment criteria (n = 80). The experimental design was formulated prior to recruitment, and analysis was conducted from June 2016 to March 2017.Main outcomes and measuresAlterations in umbilical cord whole-blood miRNA expression.ResultsFrom 170 neonates, 160 were included in the final analysis. The BiHiVE1 cohort included 87 infants (21 control infants, 39 infants with PA, and 27 infants with HIE), and BiHiVE2 included 73 infants (control [n = 22], PA [n = 26], and HIE [n = 25]). The BiHiVE1 and BiHiVE2 had a median age of 40 weeks (interquartile range [IQR], 39-41 weeks) and 40 weeks (IQR, 39-41 weeks), respectively, and included 56 boys and 31 girls and 45 boys and 28 girls, respectively. In BiHiVE1, 12 candidate miRNAs were identified, and 7 of these miRNAs were chosen for validation in BiHiVE2. The BiHiVE2 cohort showed consistent alteration of 3 miRNAs; miR-374a-5p was decreased in infants diagnosed as having HIE compared with healthy control infants (median relative quantification, 0.38; IQR, 0.17-0.77 vs 0.95; IQR, 0.68-1.19; P = .009), miR-376c-3p was decreased in infants with PA compared with healthy control infants (median, 0.42; IQR, 0.21-0.61 vs 0.90; IQR, 0.70-1.30; P = .004), and mir-181b-5p was decreased in infants eligible for TH (median, 0.27; IQR, 0.14-1.41) vs 1.18; IQR, 0.70-2.05; P = .02).Conclusions and relevanceAltered miRNA expression was detected in umbilical cord blood of neonates with PA and HIE. These miRNA could assist diagnostic markers for early detection of HIE and PA at birth.

Dataset Information

Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety.

Publications

Autologous cord blood cell therapy for neonatal hypoxic-ischaemic encephalopathy: a pilot study for feasibility and safety.

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