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©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
Feasibility of allogeneic mesenchymal stem cells in pediatric hypoxic-ischemic encephalopathy: Phase I study
Serdar Kabatas, Erdinç Civelek, Eyüp Can Savrunlu, Necati Kaplan, Osman Boyalı, Furkan Diren, Halil Can, Ali Genç, Tunç Akkoç, Erdal Karaöz
Serdar Kabatas, Erdinç Civelek, Eyüp Can Savrunlu, Osman Boyalı, Furkan Diren, Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Istanbul 34255, Turkey
Serdar Kabatas, Erdinç Civelek, Pediatric Allergy-Immunology, Marmara University, Institute of Health Sciences, Istanbul 34854, Turkey
Serdar Kabatas, Center for Stem Cell & Gene Therapy Research and Practice, University of Health Sciences, Istanbul 34255, Turkey
Necati Kaplan, Department of Neurosurgery, Istanbul Rumeli University, Çorlu Reyap Hospital, Tekirdağ 59860, Turkey
Halil Can, Department of Neurosurgery, Istanbul Biruni University, Faculty of Medicine, Istanbul 34010, Turkey
Halil Can, Department of Neurosurgery, Istanbul Medicine Hospital, Istanbul 34203, Turkey
Ali Genç, Department of Neurosurgery, Istanbul Asya Hospital, Istanbul 34250, Turkey
Tunç Akkoç, Pediatric Allergy-Immunology, Marmara University, Istanbul 34899, Turkey
Erdal Karaöz, Center for Regenerative Medicine and Stem Cell Research & Manufacturing (LivMedCell), Liv Hospital, Istanbul 34340, Turkey
Erdal Karaöz, Department of Histology and Embryology, Istinye University, Faculty of Medicine, Istanbul 34010, Turkey
Erdal Karaöz, Center for Stem Cell and Tissue Engineering Research and Practice, Istinye University, Istanbul 34340, Turkey
Author contributions: Kabataş S, Karaöz E, and Akkoç T performed concept and design of the study; Kabataş S, Civelek E, Karaöz E, and Akkoç T performed the supervision; Kabataş S, Civelek E, Kaplan N, Savrunlu EC, Can H, Genç A, Boyalı O, Diren F performed the analysis and/or interpretation; Kabataş S, Civelek E, Can H, Genç A, Boyalı O, Diren F, Karaöz E performed the literature search; Kabataş S, Kaplan N, Savrunlu EC, Karaöz E, and Akkoç T was responsible for writing; Kabatas S, Civelek E, Savrunlu EC, Karaöz E, and Akkoç T conducted critical reviews.
Institutional review board statement: Ethical approval to report this case was obtained from the IRB of Turkish Ministry of Health, Department of Organ, Tissue Transplant and Dialysis Services’ Scientific Committee, Ankara, Turkey, No. 56733164-203-E. 2351.
Informed consent statement: There is human subject in this article and written informed consents were obtained from the patient for their anonymized information to be published in this article and before the stem cell therapies.
Conflict-of-interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
http://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Serdar Kabatas, MD, Full Professor, Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Karayolları Mahallesi, Osmanbey Caddesi 616. Sokak No. 10, Gaziosmanpaşa, Istanbul 34255, Turkey.
kabatasserdar@hotmail.com
Received: December 24, 2020
Peer-review started: December 24, 2020
First decision: February 14, 2021
Revised: February 26, 2021
Accepted: April 22, 2021
Article in press: April 22, 2021
Published online: May 26, 2021
Processing time: 152 Days and 10.7 Hours
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 × 106/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.
Core Tip: Hypoxic-ischemic encephalopathy (HIE) emerges as one of the leading causes of morbidity and mortality in children. There are a limited number of options for treating HIE. Recently, stem cell and cellular therapies appear to be a potential treatment option for ischemic brain injury caused by HIE. The aim of this phase I open-label clinical study is to investigate the efficacy and safety of one of these stem cell-based therapies in a group of pediatric patients with HIE. Both the triple-route and multiple Wharton`s jelly-derived mesenchymal stem cells administrations were safe and effective in pediatric patients with HIE with significant neurological and functional improvements.
