Future perspectives of cell therapy for neonatal hypoxic–ischemic encephalopathy

Nabetani, Makoto; Shintaku, Haruo; Hamazaki, Takashi

doi:10.1038/pr.2017.260

Cited by 44 publications

(34 citation statements)

References 92 publications

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“…The cell dose was not adjusted in each case. Previously, we evaluated the quality of the processed UCB using UCB collected from volunteers and confirmed the sterility, low haemolysis, and high cell viability, e.g., the viability of CD34 + cells was more than 90% at up to 96 hours after cell processing and storage at 4 °C of the samples 28 . Processed UCB was divided into three doses and intravenously administered at 12-24, 36-48, and 60-72 hours after the birth (Fig.…”

mentioning

confidence: 71%

“…The timings of cell infusion were extrapolated from animal studies considering the safety of noncryopreserved UCB. Some of the data of this clinical study have already been published, i.e., the brief data on early time points from five of the six cases 28 . In this article, we have presented more detailed data up to 18 months of age from all six cases.…”

Section: Discussionmentioning

confidence: 99%

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

Tsuji

Sawada

Watabe

et al. 2020

Sci Rep

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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 preand 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. Acute brain dysfunction may occur unexpectedly during and immediately after birth. Brain dysfunction noted immediately after birth, from any cause, is collectively termed neonatal encephalopathy 1. The signs and symptoms of neonatal encephalopathy include altered levels of consciousness, weak muscle tone, impaired feeding, respiratory distress, and seizures. In many infants with neonatal encephalopathy, the pivotal pathophysiology is an insufficient supply of blood flow and oxygen to the brain in the ante-, intra-, or very immediate postpartum period. In these cases, neonatal encephalopathy is named hypoxic-ischaemic encephalopathy (HIE) 2. Mild hypothermia is the only therapy proven effective for term newborns with HIE 3,4. Even if infants with HIE receive therapeutic hypothermia, 40-44% die or survive with severe neurological impairments, including cerebral palsy and intellectual disability 3,4. The therapeutic time window is within 6 hours after birth for hypothermia to be effective 3,5,6. Hence, it is an urgent task to develop a novel therapy for HIE, especially a therapy with a long therapeutic time window 7. Cell-based therapy has attracted much attention because of not only its regenerative property but also its long therapeutic time window 8. Preclinical studies with animal models with neonatal encephalopathy show that cell therapies initiated hours or days after the injury are beneficial. Although a variety of cell therapies have been

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confidence: 71%

Section: Discussionmentioning

confidence: 99%

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

Tsuji

Sawada

Watabe

et al. 2020

Sci Rep

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“…Some clinical trials are underway in HIE and cerebral palsy contexts, with this approach able to be used not only in the strict time window proposed for TH but even in a longer period. The suggested protective mechanism of stem cell therapy operates at several levels, being able to modulate/interact with inflammation, apoptosis, and oxidative stress, but also enhancing regeneration [19].…”

Section: Therapeutic Strategies For Hiementioning

confidence: 99%

Exploring Perinatal Asphyxia by Metabolomics

et al. 2020

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Brain damage related to perinatal asphyxia is the second cause of neuro-disability worldwide. Its incidence was estimated in 2010 as 8.5 cases per 1000 live births worldwide, with no further recent improvement even in more industrialized countries. If so, hypoxic-ischemic encephalopathy is still an issue of global health concern. It is thought that a consistent number of cases may be avoided, and its sequelae may be preventable by a prompt and efficient physical and therapeutic treatment. The lack of early, reliable, and specific biomarkers has up to now hampered a more effective use of hypothermia, which represents the only validated therapy for this condition. The urge to unravel the biological modifications underlying perinatal asphyxia and hypoxic-ischemic encephalopathy needs new diagnostic and therapeutic tools. Metabolomics for its own features is a powerful approach that may help for the identification of specific metabolic profiles related to the pathological mechanism and foreseeable outcome. The metabolomic profiles of animal and human infants exposed to perinatal asphyxia or developing hypoxic-ischemic encephalopathy have so far been investigated by means of 1 H nuclear magnetic resonance spectroscopy and mass spectrometry coupled with gas or liquid chromatography, leading to the identification of promising metabolomic signatures. In this work, an extensive review of the relevant literature was performed.trigger several changes at molecular and cellular levels, which may end in cell death and in local/systemic inflammation. The shortage of oxygen, which acts as final electron acceptor in the electron transport chain (ETC) during aerobic respiration, induced by hypoxia and by ischemia, boosts reactive oxygen species (ROS) generation at the cellular level. Generated ROS attack surrounds components at both the mitochondrial and cellular level, leading to mitochondrial dysfunction and permanent damage to cells. The pathogenesis of HIE is strongly influenced by the failure of several potent fetal compensatory mechanisms to cope with the 'physiological' hypoxia during pregnancy and delivery. The final clinical outcome of such an insult is a wide spectrum of neurological deficits, ranging from behavioral and motor impairments to general developmental delays to seizures related to structural brain damage.The severity of the clinical picture of HIE infants is the final result of an uneven combination of several factors, and among them the length and strength of hypoxic insult, together with fetal metabolic conditions before the hypoxia onset. For this reason, the pathological effects are complex to forecast, and they evolve over time. They may be related to two main pathological phases: A primary and a secondary energy failure. Primary energy failure is the first biological effect of both hypoxia and a reduction of cerebral blood flow and it mainly takes place before birth. While the impairment of blood flow is responsible for the progressive reduction of glucose availability needed to fuel brain cells' metabo...

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“…Preclinical studies have been done evaluating stem cells in neonatal brain injury. Cord blood stem cell therapy has could have protective effects mainly on inflammation, apoptosis, oxidative stress, and may enhance regeneration [ 46 ]. Unlike hypothermia, cell based therapy may provide a longer therapeutic window as repair and regeneration take place over longer periods of time.…”

Section: Emerging Therapiesmentioning

confidence: 99%

Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates

2018

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Neonatal hypoxic ischemic encephalopathy (HIE) presents a significant clinical burden with its high mortality and morbidity rates globally. Therapeutic hypothermia (TH) is now standard of care for infants with moderate to severe HIE, but has not definitively changed outcomes in severe HIE. In this review, we discuss newer promising markers that may help the clinician identify severity of HIE. Therapies that are beneficial and agents that hold promise for neuroprotection are described, both for use either alone or as adjuncts to TH. These include endogenous pathway modifiers such as erythropoietin and analogues, melatonin, and remote ischemic post conditioning. Stem cells have therapeutic potential in this condition, as in many other neonatal conditions. Of the agents listed, only erythropoietin and analogues are currently being evaluated in large randomized controlled trials (RCTs). Exogenous therapies such as argon and xenon, allopurinol, monosialogangliosides, and magnesium sulfate continue to be investigated. The recognition of tertiary mechanisms of brain damage has opened up new research into therapies not only to attenuate brain damage but also to promote cell repair and regeneration in a developmentally disorganized brain long after the perinatal insult. These alternative modalities may be especially important in mild HIE and in areas of the world where there is limited access to expensive hypothermia equipment and services.

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Future perspectives of cell therapy for neonatal hypoxic–ischemic encephalopathy

Cited by 44 publications

References 92 publications

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

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

Exploring Perinatal Asphyxia by Metabolomics

Current and Emerging Therapies in the Management of Hypoxic Ischemic Encephalopathy in Neonates

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