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Journal of Neurorestoratology  2018, Vol. 6 Issue (1): 74-80    doi: 10.26599/JNR.2018.9040002
Clinical Trial Design     
Neurorestorative effect of olfactory ensheathing cells and Schwann cells by intranasal delivery for patients with ischemic stroke: design of a multicenter randomized double-blinded placebo-controlled clinical study
Gengsheng Mao1,2,(✉), Yunliang Wang3, Xiaoling Guo4, Jun Liu5, Zuncheng Zheng6, Lin Chen7
1 Institute of Neurorestoratology, General Hospital of Chinese people’s Armed Police Forces, Beijing 100039, China
2 Beijing Hongtianji Neuroscience Academy, Beijing 100043, China
3 Neuorlogical Center, 148 Hospital of Chinese PLA, Zhibo of Shandong, China
4 Neurological Department, 266 Hospital of Chinese PLA, Chengde of Hebei, China
5 Neurological Department, Civil Aviation Guangzhou Hospital
6 Department of rehabilitation, Taian Central Hospital, Taian of Shadong, China
7 Department of Neurosurgery,Tsinghua University Yuquan Hospital
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Abstract  Introduction:

There have been many clinical studies or trials for patients with ischemic stroke by cell therapy, which includes olfactory ensheathing cell (OEC), mononuclear cell, mesenchymal stromal cell, fetal neural cell or products of varying stem cells, etc. Those cells through different transplanting ways have showed moderate neurorestorative effect in patients with ischemic stroke, but majority were not multicenter randomized, double-blinded, placebo-controlled studies or trials. OEC transplantation has shown a more effective to restore neurological damage in central nervous system (CNS). We hypothesize that OEC through intra-olfactory mucosa transplantation can migrate into the ischemic stroke area around and restore neurological deficit caused from this disaster.

Objective of the study:

This is a multicenter, randomized, double-blinded, placebo- controlled 12 month clinical study of OECs and Schwann cells (SCs) for patients with sub-acute ischemic stroke and chronic ischemic stroke, to test which kind of cell has more neurorestorative effect for patients with ischemic stroke relative to placebo.

Design of the study:

This study is involved two groups of patients with sub-acute ischemic stroke and chronic ischemic stroke. Each group enrolls 30 patients. The experimental intervention consists in using OECs and SCs through intra-olfactory mucosa transplantation in participating patients. This will be compared with using placebo (injecting cell culture medium). Participating patients in groups of sub-acute ischemic stroke and chronic ischemic stroke are randomized in natural order to divide into A, B, or C groups and get one of experimental treatment procedures. Patients, operating physicians, and assessing physicians are left unaware of what cells or medium will be injected to participating patients. All patients will be assessed before treatment and after one month, three months, six months, and one year.

Ethics and dissemination:

The clinical study protocol and consent form were approved by Chinese Association of Neurorestoratology and the ethics committees of the hospitals which joined this clinical study. Findings will be published in peer-reviewed journals.

Key wordsneurorestorative effect      cell therapy      stroke      olfactory ensheathing cell      schwann cell,neurorestoratology     
Received: 26 November 2017      Published: 25 June 2018
Corresponding Authors: Gengsheng Mao   
Cite this article:

Gengsheng Mao, Yunliang Wang, Xiaoling Guo, Jun Liu, Zuncheng Zheng, Lin Chen. Neurorestorative effect of olfactory ensheathing cells and Schwann cells by intranasal delivery for patients with ischemic stroke: design of a multicenter randomized double-blinded placebo-controlled clinical study. Journal of Neurorestoratology, 2018, 6: 74-80.

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[1] Howard G, Goff DC. Population shifts and the future of stroke: forecasts of the future burden of stroke. Ann N Y Acad Sci. 2012, 1268: 14-20.
[2] Feigin VL, Forouzanfar MH, Krishnamurthi R, et al. Global and regional burden of stroke during 1990-2010: Findings from the Global Burden of Disease Study 2010. Lancet 2014, 383(9913): 245-254.
[3] Qiao L, Lu J, Huang H. Clinical neurorestorative progress in stroke. Journal of Neurorestoratology, 2015: 363-371.
[4] Chen L, Xi H, Huang H, et al. Multiple cell transplantation based on an intraparenchymal approach for patients with chronic phase stroke. Cell Transplant 2013, 22(): 83-91.
[5] Mendon?a ML, Freitas GR, Silva SA, et al. Safety of intra-arterial autologous bone marrow mononuclear cell transplantation for acute ischemic stroke. Arq Bras Cardiol. 2006, 86(1): 52-55.
[6] Correa PL, Mesquita CT, Felix RM, et al. Assessment of intra-arterial injected autologous bone marrow mononuclear cell distribution by radioactive labeling in acute ischemic stroke. Clin Nucl Med. 2007, 32(11): 839-841.
[7] Barbosa da Fonseca LM, Gutfilen B, Rosado de Castro PH, et al. Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol. 2010, 221(1): 122-128.
[8] Battistella V, de Freitas GR, da Fonseca LM, et al. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen Med. 2011, 6(1): 45-52.
[9] Friedrich MA, Martins MP, Araújo MD, et al. Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. Cell Transplant. 2012, 21(): S13-S21.
[10] Moniche F, Gonzalez A, Gonzalez-Marcos JR, et al. Intra- arterial bone marrow mononuclear cells in ischemic stroke: a pilot clinical trial. Stroke 2012, 43(8): 2242-2244.
[11] Moniche F, Escudero I, Zapata-Arriaza E, et al. Intra- arterial bone marrow mononuclear cells (BM-MNCs) transplantation in acute ischemic stroke (IBIS trial): Protocol of a phase II, randomized, dose-finding, controlled multicenter trial. Int J Stroke 2015, 10(7): 1149-1152.
[12] Savitz SI, Misra V, Kasam M, et al. Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol. 2011, 70(1): 59-69.
[13] Prasad K, Mohanty S, Bhatia R, et al. Autologous intravenous bone marrow mononuclear cell therapy for patients with subacute ischaemic stroke: A pilot study. Indian J Med Res. 2012, 136(2): 221-228.
[14] Prasad K, Sharma A, Garg A, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: A multicentric, randomized trial. Stroke 2014, 45(12): 3618-3624.
[15] Rosado-de-Castro PH, Schmidt Fda R, Battistella V, et al. Biodistribution of bone marrow mononuclear cells after intra-arterial or intravenous transplantation in subacute stroke patients. Regen Med. 2013, 8(2): 145-155.
[16] Vasconcelos-dos-Santos A, Rosado-de-Castro PH, Lopes de Souza SA, et al. Intravenous and intra-arterial administration of bone marrow mononuclear cells after focal cerebral ischemia: Is there a difference in biodistribution and efficacy? Stem Cell Res. 2012, 9(1): 1-8.
[17] Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006, 8(4): 315-317.
[18] Galipeau J, Krampera M, Barrett J, et al. International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 2016, 18(2): 151-159.
[19] Bang OY, Lee JS, Lee PH, et al. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005, 14: 874-882.
[20] Bhasin A, Srivastava MV, Kumaran SS, et al. Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra. 2011, 14: 93-104.
[21] Honmou O, Houkin K, Matsunaga T, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain 2011, 134(Pt 6): 1790-1807.
[22] Lee JS, Hong JM, Moon GJ, et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 2010, 28(6): 1099-1106.
[23] Sprigg N, Bath PM, Zhao L, et al. Granulocyte-colony- stimulating factor mobilizes bone marrow stem cells in patients with subacute ischemic stroke: the stem cell trial of recovery enhancement after stroke (STEMS) pilot randomized, controlled trial (ISRCTN 16784092). Stroke 2006, 14: 2979-2983.
[24] Suárez-Monteagudo C, Hernández-Ramírez P, Alvarez- González L, et al. Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci. 2009, 27(3): 151-161.
[25] Kim SJ, Moon GJ, Chang WH, et al. Intravenous transplantation of mesenchymal stem cells preconditioned with early phase stroke serum: Current evidence and study protocol for a randomized trial. Trials. 2013, 14(1): 317-328.
[26] Tsang KS, Ng CPS, Zhu XL, et al. Phase I/II randomized controlled trial of autologous bone marrow-derived mesenchymal stem cell therapy for chronic stroke. World J Stem Cells. 2017, 9(8): 133-143.
[27] Bhasin A, Kumaran SS, Bhatia R, et al. Safety and feasibility of autologous mesenchymal stem cell transplantation in chronic stroke in Indian patients. A four-year follow up. J Stem Cells Regen Med. 2017, 13(1): 14-19.
[28] Chen DC, Lin SZ, Fan JR, et al. Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized phase II study. Cell Transplant. 2014, 23(12): 1599-1612.
[29] Wang L, Ji H, Li M, et al. Intrathecal administration of autologous CD34 positive cells in patients with past cerebral infarction: a safety study. ISRN Neurol. 2013, 2013: 128591.
[30] Díez-Tejedor E, Gutiérrez-Fernández M, Martínez-Sánchez P, et al. Reparative therapy for acute ischemic stroke with allogeneic mesenchymal stem cells from adipose tissue: a safety assessment: A phase II randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. J Stroke Cerebrovasc Dis. 2014, 23(10): 2694-2700.
[31] Jiang Y, Zhu W, Zhu J, et al. Feasibility of delivering mesenchymal stem cells via catheter to the proximal end of the lesion artery in patients with stroke in the territory of the middle cerebral artery. Cell Transplant. 2013, 22(12): 2291-2298.
[32] Qiao LY, Huang FJ, Zhao M, et al. A two-year follow-up study of co-transplantation with neural stem/precursor cells and mesenchymal stromal cells in ischemic stroke patients. Cell Transplant. 2014, 23(): S65-S72.
[33] Kondziolka D, Wechsler L, Goldstein S, et al. Transplantation of cultured human neuronal cells for patients with stroke. Neurology. 2000, 55: 565-569.
[34] Kondziolka D, Steinberg GK, Wechsler L, et al. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg. 2005, 103(1): 38-45.
[35] Meltzer CC, Kondziolka D, Villemagne VL, et al. Serial [18F] fluorodeoxyglucose positron emission tomography after human neuronal implantation for stroke. Neurosurgery. 2001, 49(3): 586-591.
[36] Nelson PT, Kondziolka D, Wechsler L, et al. Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation. Am J Pathol. 2002, 160(4): 1201-1206.
[37] Stilley CS, Ryan CM, Kondziolka D, et al. Changes in cognitive function after neuronal cell transplantation for basal ganglia stroke. Neurology. 2004, 63(7): 1320-1322.
[38] Kalladka D, Sinden J, Pollock K, et al. Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study. Lancet 2016, 388(10046): 787-796.
[39] Steinberg GK, Kondziolka D, Wechsler LR, et al. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: A phase 1/2a study. Stroke 2016, 47(7): 1817-1824.
[40] Chernykh ER, Shevela EY, Starostina NM, et al. Safety and therapeutic potential of M2 macrophages in stroke treatment. Cell Transplant. 2016, 25(8): 1461-1471.
[41] Hess DC, Wechsler LR, Clark WM, et al. Safety and efficacy of multipotent adult progenitor cells in acute ischaemic stroke (MASTERS): A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2017, 16(5): 360-368.
[42] Huang H, Chen L, Wang H, et al. Influence of patients' age on functional recovery after transplantation of olfactory ensheathing cells into injured spinal cord injury. Chin Med J (Engl). 2003, 116(10): 1488-1491.
[43] Xi H, Chen L, Huang H, et al. Preliminary report of multiple cell therapy for patients with multiple system atrophy. Cell Transplant. 2013, 22(): S93-99.
[44] Huang H, Chen L, Xi H, et al. Olfactory ensheathing cells transplantation for central nervous system diseases in 1,255 patients. Chinese Journal of Reparative And Reconstructive Surgery 2009, 23(1): 14-20.
[45] Huang H, Chen L, Xi H, et al. Fetal olfactory ensheathing cells transplantation in amyotrophic lateral sclerosis patients: a controlled pilot study. Clin Transplant. 2008, 22(6): 710-718.
[46] Chen L, Chen D, Xi H, et al. Olfactory ensheathing cell neurorestorotherapy for amyotrophic lateral sclerosis patients: benefits from multiple transplantations. Cell Transplant. 2012, 21(): S65-77.
[47] Chen L, Huang H, Xi H, et al. Intracranial transplant of olfactory ensheathing cells in children and adolescents with cerebral palsy: a randomized controlled clinical trial. Cell Transplant 2010, 9(2): 185-191.
[48] Danielyan L, Sch?fer R, von Ameln-Mayerhofer A, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol. 2009, 88(6): 315-324
[49] Sun J, Wei ZZ, Gu X, et al. Intranasal delivery of hypoxia-preconditioned bone marrow-derived mesenchymal stem cells enhanced regenerative effects after intracerebral hemorrhagic stroke in mice. Exp Neurol. 2015, 272: 78-87.
[50] Wei ZZ, Gu X, Ferdinand A, et al. Intranasal delivery of bone marrow mesenchymal stem cells improved neurovascular regeneration and rescued neuropsychiatric deficits after neonatal stroke in rats. Cell Transplant. 2015, 24(3): 391-402.
[51] Huang H Chen L. Neurorestorative process, law, and mechanisms. Journal of Neurorestoratology 2015: 23-30.
[52] Huang H, Mao G, Chen L, et al. Progress and challenges with clinical cell therapy in neurorestoratology. J Neurorestoratol. 2015: 91-95.
[53] Wang H, Ren Y, Tian G, et al. Isolation, culture and immunological characteristics of adult nasal olfactory mucosa cells: Journal of Anatomy. 2010: 374-378.
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