Feasibility of allogeneic mesenchymal stem cells in pediatric hypoxic-ischemic encephalopathy: Phase I study

Abstract

BACKGROUND Hypoxic-ischemic encephalopathy (HIE) is one of the leading causes of death and long-term neurological impairment in the pediatric population. Despite a limited number of treatments to cure HIE, stem cell therapies appear to be a potential treatment option for brain injury resulting from HIE. AIM To investigate the efficacy and safety of stem cell-based therapies in pediatric patients with HIE. METHODS The study inclusion criteria were determined as the presence of substantial deficit and disability caused by HIE. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) were intrathecally (IT), intramuscularly (IM), and intravenously administered to participants at a dose of 1 × 10 6 /kg for each administration route twice monthly for 2 mo. In different follow-up durations, the effect of WJ-MSCs administration on HIE, the quality of life, prognosis of patients, and side effects were investigated, and patients were evaluated for neurological, cognitive functions, and spasticity using the Wee Functional Independence Measure (Wee FIM) Scale and Modified Ashworth (MA) Scale. RESULTS For all participants ( n = 6), the mean duration of exposure to hypoxia was 39.17 + 18.82 min, the mean time interval after HIE was 21.83 ± 26.60 mo, the mean baseline Wee FIM scale score was 13.5 ± 0.55, and the mean baseline MA scale score was 35 ± 9.08. Three patients developed only early complications such as low-grade fever, mild headache associated with IT injection, and muscle pain associated with IM injection, all of which were transient and disappeared within 24 h. The treatment was evaluated to be safe and effective as demonstrated by magnetic resonance imaging examinations, electroencephalographies, laboratory tests, and neurological and functional scores of patients. Patients exhibited significant improvements in all neurological functions through a 12-mo follow-up. The mean Wee FIM scale score of participants increased from 13.5 ± 0.55 to 15.17 ± 1.6 points (mean ± SD) at 1 mo (z = - 1.826, P = 0.068) and to 23.5 ± 3.39 points at 12 mo (z = -2.207, P = 0.027) post-treatment. The percentage of patients who achieved an excellent functional improvement (Wee FIM scale total score = 126) increased from 10.71% (at baseline) to 12.03% at 1 mo and to 18.65% at 12 mo post-treatment. CONCLUSION Both the triple-route and multiple WJ-MSC implantations were safe and effective in pediatric patients with HIE with significant neurological and functional improvements. The results of this study support conducting further randomized, placebo-controlled studies on this treatment in the pediatric population.

Allogeneic mesenchymal stem cells may be a viable treatment modality in cerebral palsy

“…These explants were placed in dishes and cultured under humanized culture conditions at 37 °C with 5% CO 2 until the cells displaced. The resulting cells were collected when they reached 70% to 80% confluence and subjected to characterization tests at Passage 3[ 27 ]. Quality control and assurance was performed by the Pharmaceuticals and Medical Devices Agency.…”

“…Determination of UC-MSCs by flow cytometry: Expressed surface antigens were analyzed by flow cytometry, which revealed that cells were consistently positive for CD44, CD73, CD90, and CD105 and negative for hematopoietic lineage markers of CD34, CD45, and human leukocyte antigen DR2 (Figure 1 ). Telomerase activity was stable in culture conditions with a large and flat cellular morphology[ 27 ].…”

“…Cell differentiation and karyotyping: We identified some stem cell expressions and the differentiation markers of TERT, SOX2, POU5F1, CD44, ZFP42, VIM, ICAM1, THY1, VCAM1, BMP2, RUNX-1, and NES. Differentiation analyses confirmed that these cells had a trilineage (chondrocytes, osteoblasts, and adipocytes) differentiation capacity[ 27 ]. Karyotyping studies revealed no numerical or structural chromosomal abnormalities.…”

The fate and prospects of stem cell therapy in the treatment of hypoxic–ischemic encephalopathy

“…In addition, some stem cells, such as Wharton's jelly‐derived mesenchymal stem cells (WJ‐MSCs), were implanted to participants intrathecally, intramuscularly and intravenously at a dose of 1 × 10 6 /kg for each administration route twice per month in a 2‐month duration and autologous UCBC therapy in phase I and pilot study manifested good results in treating paediatric patients suffered HIE, particularly showing neurological and functional recovery, which helped facilitate future randomized, placebo‐controlled studies in tacking health issues with paediatric patients (Kabataş et al, 2018; Kabatas et al, 2021; Tsuji et al, 2020; Yang et al, 2018). A recent research confirmed that the incorporation of autologous umbilical cord with hypothermia had a better effect on the adoption of hypothermia alone (Cotten et al, 2014).…”

Neonatal Hypoxic–Ischemic Encephalopathy: Perspectives of Neuroprotective and Neuroregenerative Treatments

“…132 Additionally, a phase-I open label clinical trial evaluated the feasibility, safety, and efficacy of Wharton's jelly-derived MSC dose of 10 6 cells/kg that administered twice a month for 2 months by different routes (intrathecally, intramuscularly, and intravenously) in pediatric patients with previous hypoxic-ischemic event; six children were included with age 12 years, demonstrating a safety profile with mild side effects, such as mild fever, headache, and muscle pain, whit rapid resolution after the first 24 hours of administration. 133 The advantages of MSC treatment in newborns who suffer HIE are the easy isolation with no ethical concerns because are obtained from discarded neonatal tissues placenta or umbilical cord, reduced risk of immune reaction for autologous transplantation, and avoid the risk of tumor formation unlike embryonic stem cells. 126 However, the encouraging results of more studies are needed for standardization of the safe dose, route of administration, and window of treatment.…”