Every year in the UK, around 44 to 53 percent of babies who survive oxygen deprivation at birth still suffer lasting brain damage and cerebral palsy, despite the standard treatment of therapeutic cooling. This project addresses that gap. Cooling the baby’s body by three degrees for three days reduces injury, but it does not work for everyone—especially those with severe damage or prior infection. No other therapy is currently available. The researchers propose a new approach: delivering human umbilical cord mesenchymal stem cells (huMSC) directly into the nose, where they travel to the brain and stimulate repair without replacing damaged tissue themselves. In a pilot animal model, two doses of 30 million cells given intranasally 24 hours after oxygen deprivation protected the brain, while intravenous delivery did not. If successful, this work could lead to the first clinical trials of a stem-cell therapy for neonatal encephalopathy in babies. The researchers will also test whether tiny particles called extracellular vesicles, which carry the cells’ repair signals, can achieve the same effect—potentially offering a safer, easier-to-store alternative. The result would be a new treatment option for a condition that currently leaves half of affected children with lifelong disability.
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Problems around the time of birth causing a lack of oxygen to the baby can cause disordered brain function called neonatal encephalopathy (NE), which can result in long term brain damage and cerebral palsy. Cooling a baby by 3 degrees Celsius for three days as soon as possible after birth has been shown to be safe and leads to long term brain protection and improved outcome even to school age. Cooling is endorsed by NICE and adopted in neonatal intensive care units in UK for moderate to severe NE. However, although cooling is a major step forward for babies with NE, 44-53% still have adverse outcomes. This may be because cooling may be less effective with severe injury or there was prior exposure to infection and inflammation. Supplemental interventions to improve outcomes with and without cooling are greatly needed. Over the last 10 years, several therapeutic agents have been studied as adjuncts to HT for babies, such as erythropoietin, melatonin, allopurinol, but there is currently no therapy apart from cooling for NE. The use of stem cells to successfully treat neonatal brain injury is emerging as a promising therapy. Human umbilical cord mesenchymal stem cells (huMSC) self renew and stimulate host brain cells to regenerate and repair, with superior anti-inflammatory properties than MSC from adult tissues. Importantly, although huMSC do not survive long term and replace damaged tissues themselves, they react to the needs of the ischemic cerebral environment by secretion of growth factors, cytokines and extracellular vesicles (EVs) to regulate damage and repair. These intrinsic adaptive properties of huMSC make them excellent candidates to treat the devastating effects of NE. The newborn brain is still in a developmentally active phase, leading to high efficiency of huMSC. In a pilot pre-clinical model of NE, we observed brain protection with 2 doses of 30 million huMSC given intranasally 24h after a period of oxygen deprivation, whereas intravenous huMSC were not protective. We were able to detect these huMSC within the brain tissue. These data from male subjects suggest that huMSC (given intranasally) augment brain protection based on clinically relevant markers (recovery of aEEG and brain energy metabolism). For clinical translation, there is insufficient data on whether huMSC are protective in both normothermic and hypothermic milieu and whether there is different neuroprotective response from males and females. Recently, EVs have been identified as the key mediators of stem cell paracrine signalling. EVs deliver their contents in the form of proteins, lipids, and nucleic acids; they overcome some limitations of cell therapies, including easier storage, low immunogenicity, passage through small vessels and no tumorigenic potential. We propose the following 3 milestones as preparation for future clinical trials in babies with NE. The first milestone will prepare the huMSC and EVs. We have access to clinical-grade huMSC manufactured by UCL. The second and key milestone will assess safety and efficacy of 2 doses huMSC given intranasally at 12 and 36h after oxygen deprivation in both male and female subjects with and without cooling. We will assess outcome based on aEEG recovery, brain energy metabolism and histology. If positive we will meet MHRA with the aim to move to clinical trials. The third milestone will assess safety and efficacy of 2 doses of EVs given intranasally at 12 and 36h after oxygen deprivation. The volume of EVs that produce an equivalent anti-inflammatory effect as 30 million huMSC will be used (previously determined in vitro studies in milestone 2b). This will inform the mechanism(s) through which beneficial effects of MSC therapy are mediated and may lead to refining the strategy for future clinical trials in babies with NE.
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