Retrospective Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Exp Med. Mar 20, 2021; 11(2): 17-29
Published online Mar 20, 2021. doi: 10.5493/wjem.v11.i2.17
Phase I study on the safety and preliminary efficacy of allogeneic mesenchymal stem cells in hypoxic-ischemic encephalopathy
Serdar Kabataş, Erdinç Civelek, Necati Kaplan, Eyüp Can Savrunlu, Gülseli Berivan Sezen, Mourat Chasan, Halil Can, Ali Genç, Yener Akyuva, Osman Boyalı, Furkan Diren, Erdal Karaoz
Serdar Kabataş, Erdinç Civelek, Eyüp Can Savrunlu, Gülseli Berivan Sezen, Mourat Chasan, Osman Boyalı, Furkan Diren, Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, İstanbul 34255, Turkey
Serdar Kabataş, Erdinç Civelek, Pediatric Allergy-Immunology, Marmara University, Institute of Health Sciences, İstanbul 34854, Turkey
Serdar Kabataş, Center for Stem Cell and Gene Therapy Research and Practice, University of Health Sciences, İstanbul 34255, Turkey
Necati Kaplan, Department of Neurosurgery, Istanbul Rumeli University, Çorlu Reyap Hospital, Tekirdağ 59860, Turkey
Halil Can, Department of Neurosurgery, İstanbul Biruni University, Faculty of Medicine, İstanbul 34010, Turkey
Halil Can, Department of Neurosurgery, İstanbul Medicine Hospital, İstanbul 34203, Turkey
Ali Genç, Department of Neurosurgery, İstanbul Asya Hospital, İstanbul 34250, Turkey
Yener Akyuva, Department of Neurosurgery, Mustafa Kemal University, Faculty of Medicine, Hatay 31060, Turkey
Erdal Karaoz, Center for Regenerative Medicine and Stem Cell Research and Manufacturing (LivMedCell), Liv Hospital, İstanbul 34340, Turkey
Erdal Karaoz, Department of Histology and Embryology, İstinye University, Faculty of Medicine, İstanbul 34010, Turkey
Erdal Karaoz, Center for Stem Cell and Tissue Engineering Research and Practice, İstinye University, İstanbul 34340, Turkey
Author contributions: Kabataş S, Karaöz E were responsible for the concept and design; Kabataş S, Civelek E and Karaöz E in charge of supervision; Kabataş S, Civelek E, Kaplan N, Savrunlu EC, Sezen GB, Chasan M, Can H, Genç A, Akyuva Y, Boyalı O and Diren F accomplished analysis and/or interpretation; Kabataş S, Civelek E, Sezen GB, Chasan M, Can H, Genç A, Akyuva Y, Boyalı O, Diren F and Karaöz E were responsible for literature searching; Kabataş S, Kaplan N, Savrunlu EC and Karaöz E were responsible for writing manuscripts; Kabatas K, Civelek E, Kaplan N, Savrunlu EC and Karaöz E were responsible for critical reviews.
Institutional review board statement: Approval for the trial was obtained from the Turkish Ministry of Health, General Directorate of Health Services, Department of Organ/Tissue Transplantation and Dialysis Services, and the Scientific Committee (No. 56733164-203-E.2569).
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 Kabataş, MD, PhD, Chairman, Full Professor, Department of Neurosurgery, University of Health Sciences, Gaziosmanpaşa Training and Research Hospital, Serdar Kabataş, Karayolları Mahallesi, Osmanbey Caddesi 616, İstanbul 34255, Turkey. kabatasserdar@gmail.com
Received: December 24, 2020
Peer-review started: December 24, 2020
First decision: January 18, 2021
Revised: February 19, 2021
Accepted: March 12, 2021
Article in press: March 12, 2021
Published online: March 20, 2021
Processing time: 83 Days and 16.9 Hours
Abstract
BACKGROUND

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of morbidity and mortality in the adult as well as in the neonate, with limited options for treatment and significant dysfunctionality.

AIM

To investigate the safety and preliminary efficacy of allogeneic mesenchymal stem cells (MSCs) in HIE patients.

METHODS

Patients who had HIE for at least 6 mo along with significant dysfunction and disability were included. All patients were given Wharton’s jelly-derived MSCs at 1 × 106/kg intrathecally, intravenously, and intramuscularly twice a month for two months. The therapeutic effects and prognostic implications of MSCs were evaluated by multiple follow-ups. Functional independence measure (FIM), modified Ashworth, and Karnofsky scales were used to assess any side effects, neurological and cognitive functions, and overall outcomes.

RESULTS

The 8 subjects included in the study had a mean age of 33.25 ± 10.18 years. Mean HIE exposure and mean post-HIE durations were 45.63 ± 10.18 and 19.67 ± 29.04 mo, respectively. Mean FIM score was 18.38 ± 1.06, mean modified Ashworth score was 43.5 ± 4.63, and mean Karnofsky score was 20. For the first 24 h, 5 of the patients experienced a subfebrile state, accompanied by mild headaches due to intrathecally administration and muscle pain because of intramuscularly administration. Neurological and functional examinations, laboratory tests, electroencephalography, and magnetic resonance imaging were performed to assess safety of treatment. Mean FIM score increased by 20.88 ± 3.31 in the first month (P = 0.027) and by 31.38 ± 14.69 in 12 mo (P = 0.012). The rate of patients with an FIM score of 126 increased from 14.58% to 16.57% in the first month and 24.90% in 12 mo.

CONCLUSION

Multiple triple-route Wharton’s jelly-derived MSC administrations were found to be safe for HIE patients, indicating neurological and functional improvement. Based on the findings obtained here, further randomized and placebo research could be performed.

Keywords: Hypoxic-ischemic encephalopathy; Stem cell; Transplantation; Wharton's jelly

Core Tip: Occurring due to the disruption of oxygen supply to the brain, hypoxic-ischemic encephalopathy is associated with substantial rates of morbidity and mortality. In addition to supportive therapy and symptomatic treatment, research on the treatment of hypoxic-ischemic encephalopathy has focused new therapautic strategies as stem cell therapy. This multi-center and open-label phase I study was performed to investigate the safety and preliminary efficacy of multiple triple-route Wharton’s Jelly-Derived Mesenchymal Stem Cells administrations. The patients included in this study also had improvement in modified Ashworth scores, Functional Independence Measure scores over the course of a year, indicating long-term impact on brain functions.