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 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

A protocol for cell therapy infusion in neonates

“…This study casts doubt upon the conclusions drawn from previous trials of IV cell therapy in neonates, though reports of detailed infusion protocols used during neonatal cell therapy are sparse. 7,23 Our group reported the protocol used in our first-in-human safety study of hAECs. 7 Six infants with established BPD were given 1 million hAECs/kg intravenously.…”

White matter injury in the neonatal hypoxic‐ischemic brain and potential therapies targeting microglia

“…Thus, the contributions of sexual dimorphism to myelination and microglial polarization following neonatal H‐I injury warrant further study in both sexes. Cell‐specific targeting methods are also worth considering as potential therapeutic strategies; these approaches include the site‐specific delivery of D‐NAC targeting microglia, intranasal MSC treatment, and autologous cord blood cell therapy (Donega et al., 2014; Nance et al., 2015; Tsuji et al., 2020). Ideally, the advantage of intranasal administration is that patients are able to be treated locally and avoid the side effects of drugs on peripheral organs.…”

Regeneration using endogenous neural stem cells following neonatal brain injury

“…Effects of these stem cells are due to the promotion of endogenous neurogenesis through the secretion of various growth factors, angiogenesis, and anti‐inflammatory effects, rather than differentiation of their own cells into neural cells 97 . Several clinical trials investigating the administration of UCBCs and BMSCs have shown their safety and feasibility 98–101 . However, no successful clinical method to improve neurobehavioral functions by enhancing neurogenesis has been reported.…”

“…97 Several clinical trials investigating the administration of UCBCs and BMSCs have shown their safety and feasibility. [98][99][100][101] However, no successful clinical method to improve neurobehavioral functions by enhancing neurogenesis has been reported. Combinations of the approaches mentioned above and optimization of dosages and timing of treatment is expected to lead to promising results in neonatal patients with brain injury.…”