Mesenchymal Stem Cells With Cooling Therapy for Infants With Hypoxic-Ischemic Encephalopathy

Summary

Hypoxic-ischemic encephalopathy (HIE) is a serious condition in newborns caused by lack of oxygen and blood flow around the time of birth. Standard treatment with cooling therapy (therapeutic hypothermia) lowers the risk of death or disability, but many infants still suffer long-term problems. This study will test whether adding stem cell therapy after cooling can further improve outcomes. The stem cells are taken from donated human placentas (Wharton's jelly-derived mesenchymal stem cells, MSCs). The cells are prepared under strict laboratory standards and checked for safety. Infants with moderate to severe HIE who have completed cooling will be randomly assigned to receive either three intravenous infusions of MSCs or placebo within the first 10 days of life. Each infusion is given over about 30 minutes while the infant is closely monitored. Researchers will follow participants for up to 2 years. The main outcome is whether MSC treatment can reduce the combined risk of death or serious developmental delay at 1 year of age. The study will also track brain MRI findings, safety events, and developmental progress at 2 years.

Timeline

Start

2026-06

Primary completion

2032-12

Completion

2033-12

Publications

• Background Xu J, Feng Z, Wang X, Xiong Y, Wang L, Ye L, Zhang H. hUC-MSCs Exert a Neuroprotective Effect via Anti-apoptotic Mechanisms in a Neonatal HIE Rat Model. Cell Transplant. 2019 Dec;28(12):1552-1559. doi: 10.1177/0963689719874769. Epub 2019 Sep 12.
• Results Bruschettini M, Romantsik O, Moreira A, Ley D, Thebaud B. Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants. Cochrane Database Syst Rev. 2020 Aug 19;8(8):CD013202. doi: 10.1002/14651858.CD013202.pub2.
• Results Teo EJ, Jones LE, Wixey JA, Boyd RN, Colditz PB, Bjorkman ST. Combined hypothermia and mesenchymal stem cells in animal models of neonatal hypoxic-ischaemic encephalopathy: a systematic review. Pediatr Res. 2022 Jul;92(1):25-31. doi: 10.1038/s41390-021-01716-y. Epub 2021 Sep 4.
• Results Ahn SY, Chang YS, Sung DK, Sung SI, Park WS. Hypothermia broadens the therapeutic time window of mesenchymal stem cell transplantation for severe neonatal hypoxic ischemic encephalopathy. Sci Rep. 2018 May 16;8(1):7665. doi: 10.1038/s41598-018-25902-x.
• Results Terada K, Sasaki M, Nagahama H, Kataoka-Sasaki Y, Oka S, Ukai R, Yokoyama T, Iizuka Y, Sakai T, Fukumura S, Tsugawa T, Kocsis JD, Honmou O. Therapeutic efficacy of intravenous infusion of mesenchymal stem cells in rat perinatal brain injury. Pediatr Res. 2023 Dec;94(6):1921-1928. doi: 10.1038/s41390-023-02717-9. Epub 2023 Jul 8.
• Results van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2010 Mar;24(3):387-93. doi: 10.1016/j.bbi.2009.10.017. Epub 2009 Oct 31.
• Results van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function. J Neurosci. 2010 Jul 14;30(28):9603-11. doi: 10.1523/JNEUROSCI.1835-10.2010.
• Results Wagenaar N, de Theije CGM, de Vries LS, Groenendaal F, Benders MJNL, Nijboer CHA. Promoting neuroregeneration after perinatal arterial ischemic stroke: neurotrophic factors and mesenchymal stem cells. Pediatr Res. 2018 Jan;83(1-2):372-384. doi: 10.1038/pr.2017.243. Epub 2017 Nov 1.
• Results Ahn SY, Chang YS, Sung DK, Sung SI, Ahn JY, Park WS. Pivotal Role of Brain-Derived Neurotrophic Factor Secreted by Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage in Newborn Rats. Cell Transplant. 2017 Jan 24;26(1):145-156. doi: 10.3727/096368916X692861. Epub 2016 Aug 16.
• Results Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ; Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559. doi: 10.1371/journal.pone.0047559. Epub 2012 Oct 25.
• Results Mintoft A, Vallatos A, Robertson NJ. Mesenchymal Stromal Cell therapy for Hypoxic Ischemic Encephalopathy: Future directions for combination therapy with hypothermia and/or melatonin. Semin Perinatol. 2024 Aug;48(5):151929. doi: 10.1016/j.semperi.2024.151929. Epub 2024 Jun 13.
• Results Dezawa M, Kanno H, Hoshino M, Cho H, Matsumoto N, Itokazu Y, Tajima N, Yamada H, Sawada H, Ishikawa H, Mimura T, Kitada M, Suzuki Y, Ide C. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest. 2004 Jun;113(12):1701-10. doi: 10.1172/JCI20935.
• Results Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008 Sep;8(9):726-36. doi: 10.1038/nri2395.
• Results Braccioli L, Heijnen CJ, Coffer PJ, Nijboer CH. Delayed administration of neural stem cells after hypoxia-ischemia reduces sensorimotor deficits, cerebral lesion size, and neuroinflammation in neonatal mice. Pediatr Res. 2017 Jan;81(1-1):127-135. doi: 10.1038/pr.2016.172. Epub 2016 Sep 15.
• Results Kaminski N, Koster C, Mouloud Y, Borger V, Felderhoff-Muser U, Bendix I, Giebel B, Herz J. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Reduce Neuroinflammation, Promote Neural Cell Proliferation and Improve Oligodendrocyte Maturation in Neonatal Hypoxic-Ischemic Brain Injury. Front Cell Neurosci. 2020 Dec 10;14:601176. doi: 10.3389/fncel.2020.601176. eCollection 2020.
• Results Nabetani M, Shintaku H, Hamazaki T. Future perspectives of cell therapy for neonatal hypoxic-ischemic encephalopathy. Pediatr Res. 2018 Jan;83(1-2):356-363. doi: 10.1038/pr.2017.260. Epub 2017 Nov 8.

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