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Intrathecal Injection of Allogenic Bone Marrow-Derived Mesenchymal Stromal Cells in Treatment of Patients with Severe Ischemic Stroke: Study Protocol for a Randomized Controlled Observer-Blinded Trial

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Abstract

Mesenchymal stromal cells (MSCs) can differentiate into multiple tissues. Preclinical studies have shown that MSC-based therapy is a potential new treatment approach for ischemic stroke. These results support the urgent need for further studies of MSC transplantation in the treatment of ischemic stroke in humans. Here, we develop a prospective, randomized, controlled, observer-blinded phase II trial to assess the clinical safety, feasibility, and therapeutic mechanisms of allogenic bone marrow-derived MSCs (BM-MSCs) by intrathecal infusion in the treatment of patients with cerebral infarction within the middle cerebral artery and with a National Institutes of Health Stroke Scale (NIHSS) score from 15 to 25. Sample size calculation has determined that a patient population of 118, with ischemic stroke between 30 and 90 days following onset, will be randomly divided into experimental (n = 59) and control (n = 59) groups. Then eligible patients will receive four intrathecal infusions of allogenic BM-MSCs (1 × 106 cells/kg body weight) once a week. All patients have detailed functional assessments and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. The primary outcome is the score on the modified Rankin Scale at 90 days after treatment, and the second outcomes include multiple indicators of safety and feasibility. And this trial has been registered as ChiCTR-INR-16008908 (25 July 2016).

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References

  1. Misra V, Ritchie MM, Stone LL, et al. Stem cell therapy in ischemic stroke: role of IV and intra-arterial therapy. Neurology. 2012;79(13):207–12.

    Article  Google Scholar 

  2. Chopp M, Steinberg GK, Kondziolka D, Lu M, Bliss TM, Li Y, et al. Who’s in favor of translational cell therapy for stroke: STEPS forward please? Cell Transplant. 2009;18(7):691–3.

    Article  Google Scholar 

  3. Rosado-de-Castro PH, Pimentel-Coelho PM, da Fonseca LM, et al. The rise of cell therapy trials for stroke: review of published and registered studies. Stem Cells Dev. 2013;22(15):2095–111.

    Article  Google Scholar 

  4. Maria Ferri ALBA, Lisini D, Boncoraglio G, et al. Mesenchymal stem cells for ischemic stroke: progresses and possibilities. Curr Med Chem. 2016;23(16):1598–068.

    Article  CAS  Google Scholar 

  5. Wan H, Li F, Zhu L, Wang J, Yang Z, Pan Y. Update on therapeutic mechanism for bone marrow stromal cells in ischemic stroke. J Mol Neurosci. 2013;52(2):177–85.

    Article  Google Scholar 

  6. Vu QXK, Eckert M, Zhao W, et al. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. 2014;82(14):1277–86.

    Article  Google Scholar 

  7. Bang OY, Lee JS, Lee PH, Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005;57(6):874–82.

    Article  Google Scholar 

  8. Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY, 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):1099–106.

    Article  Google Scholar 

  9. Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, et al. Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 2011;134(Pt 6):1790–807.

    Article  Google Scholar 

  10. Jiang Y, Zhu W, Zhu J, Wu L, Xu G, Liu X. 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):2291–8.

    Article  Google Scholar 

  11. Qiao LY, Huang FJ, Zhao M, et al. A two-year follow-up study of cotransplantation with neural stem/progenitor cells and mesenchymal stromal cells in ischemic stroke patients. Cell Transplant. 2014;23(Suppl 1):S65–72.

    Article  Google Scholar 

  12. Steinberg GK, Kondziolka D, Wechsler LR, Lunsford LD, Coburn ML, Billigen JB, et al. Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke. 2016;47(7):1817–24.

    Article  Google Scholar 

  13. Bhasin A, Srivastava MV, Kumaran SS, et al. Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra. 2011;1(1):93–104.

    Article  Google Scholar 

  14. Bhasin A, Kumaran SS, Bhatia R, Mohanty S, Srivastava MVP. 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):14–9.

    PubMed  PubMed Central  Google Scholar 

  15. Bang OY. Clinical trials of adult stem cell therapy in patients with ischemic stroke. J Clin Neurol. 2016;12(1):14–20.

    Article  Google Scholar 

  16. Han H, Chang SK, Chang JJ, Hwang SH, Han SH, Chun BH. Intrathecal injection of human umbilical cord blood-derived mesenchymal stem cells for the treatment of basilar artery dissection: a case report. J Med Case Rep. 2011;5:562.

    Article  Google Scholar 

  17. Yamout B, Hourani R, Salti H, Barada W, el-Hajj T, al-Kutoubi A, et al. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol. 2010;227(1–2):185–9.

    Article  CAS  Google Scholar 

  18. Mohyeddin Bonab M, Mohajeri M, Sahraian MA, Yazdanifar M, Aghsaie A, Farazmand A, et al. Evaluation of cytokines in multiple sclerosis patients treated with mesenchymal stem cells. Arch Med Res. 2013;44(4):266–72.

    Article  CAS  Google Scholar 

  19. Chotivichit A, Ruangchainikom M, Chiewvit P, Wongkajornsilp A, Sujirattanawimol K. Chronic spinal cord injury treated with transplanted autologous bone marrow-derived mesenchymal stem cells tracked by magnetic resonance imaging: a case report. J Med Case Rep. 2015;9:79.

    Article  Google Scholar 

  20. Liu J, Han D, Wang Z, Xue M, Zhu L, Yan H, et al. Clinical analysis of the treatment of spinal cord injury with umbilical cord mesenchymal stem cells. Cytotherapy. 2013;15(2):185–91.

    Article  Google Scholar 

  21. Oh KW, Moon C, Kim HY, Oh SI, Park J, Lee JH, et al. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophic lateral sclerosis. Stem Cells Transl Med. 2015;4(6):590–7.

    Article  CAS  Google Scholar 

  22. Andolina M. Treatment of spinal muscolar atrophy with intrathecal mesenchymal cells. Int J Stem Cells. 2012;5(1):73–5.

    Article  CAS  Google Scholar 

  23. Choi SW, Park KB, Woo SK, Kang SK, Ra JC. Treatment of progressive supranuclear palsy with autologous adipose tissue-derived mesenchymal stem cells. J Med Case Rep. 2014;8(1):87–91.

    Article  Google Scholar 

  24. Zhu J, Xiao Y, Li Z, et al. Efficacy of surgery combined with autologous bone marrow stromal cell transplantation for treatment of intracerebral hemorrhage. Stem Cells Int. 2015;2015:318269.

    PubMed  PubMed Central  Google Scholar 

  25. Dongmei H, Jing L, Mei X, Ling Z, Hongmin Y, Zhidong W, et al. Clinical analysis of the treatment of spinocerebellar ataxia and multiple system atrophy-cerebellar type with umbilical cord mesenchymal stromal cells. Cytotherapy. 2011;13(8):913–7.

    Article  Google Scholar 

  26. Liu L, Eckert MA, Riazifar H, et al. From blood to the brain: can systemically transplanted mesenchymal stem cells cross the blood-brain barrier? Stem Cells Int. 2013;2013:435093.

    PubMed  PubMed Central  Google Scholar 

  27. Liu X, Ye R, Yan T, Yu SP, Wei L, Xu G, et al. Cell based therapies for ischemic stroke: from basic science to bedside. Prog Neurobiol. 2014;115:92–115.

    Article  Google Scholar 

  28. Lee PH, Kim JW, Bang OY, Ahn YH, Joo IS, Huh K. Autologous mesenchymal stem cell therapy delays the progression of neurological deficits in patients with multiple system atrophy. Clin Pharmacol Ther. 2007;83(5):723–30.

    Article  Google Scholar 

  29. Walczak P, Zhang J, Gilad AA, et al. Dual-modality monitoring of targeted intra-arterial delivery of mesenchymal stem cells after transient ischemia. Stroke. 2008;35(9):1569–74.

    Article  Google Scholar 

  30. Wechsler L, Steindler D, Borlongan D, et al. Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke. 2009;40(2):510–5.

    Article  Google Scholar 

  31. Kean TJ, Lin P, Caplan AI, et al. MSCs: delivery routes and engraftment, cell-targeting strategies, and immune modulation. Stem Cells Int. 2013;36:732–42.

    Google Scholar 

  32. Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, et al. Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab. 2007;27(1):6–13.

    Article  Google Scholar 

  33. Boltze J. The dark side of the force—constraints and complications of cell therapies for stroke. Front Neurol. 2015;6(17):155.

    PubMed  PubMed Central  Google Scholar 

  34. Savitz SI, Cramer SC, Wechsler L, Consortium S. Stem cells as an emerging paradigm in stroke 3: enhancing the development of clinical trials. Stroke. 2014;45(2):634–9.

    Article  Google Scholar 

  35. Bianco P, Robey PG, Simmons PJ. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell. 2008;2(4):313–9.

    Article  CAS  Google Scholar 

  36. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2013;110(9):3507–12.

    Article  CAS  Google Scholar 

  37. Takao K, Miyakawa T. Genomic responses in mouse models greatly mimic human inflammatory diseases. Proc Natl Acad Sci U S A. 2015;112(4):1167–72.

    Article  CAS  Google Scholar 

  38. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870–947.

    Article  Google Scholar 

  39. Wu Y, Ren M, Yang R, Liang X, Ma Y, Tang Y, et al. Reduced immunomodulation potential of bone marrow-derived mesenchymal stem cells induced CCR4+CCR6+ Th/Treg cell subset imbalance in ankylosing spondylitis. Arthritis Res Ther. 2011;13(1):R29.

    Article  CAS  Google Scholar 

  40. Wang P, Li Y, Huang L, Yang J, Yang R, Deng W, et al. Effects and safety of allogenic mesenchymal stem cell intravenous infusion in active ankylosing spondylitis patients who failed NSAIDs: a 20-week clinical trial. Cell Transplant. 2014;23(10):1293–303.

    Article  Google Scholar 

  41. Prasad K, Sharma A, Garg A, Mohanty S, Bhatnagar S, Johri S, et al. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke. Stroke. 2014;45(12):3618–24.

    Article  CAS  Google Scholar 

  42. Walter SD, Gafni A, Birch S. Estimation, power and sample size calculations for stochastic cost and effectiveness analysis. PharmacoEconomics. 2007;25(6):455–66.

    Article  CAS  Google Scholar 

  43. Saver JL. Novel end point analytic techniques and interpreting shifts across the entire range of outcome scales in acute stroke trials. Stroke. 2007;38(11):3055–62.

    Article  Google Scholar 

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Funding

The study is funded by the Science and Technology Program of Guangdong province, China (no. 2015A020212018).

Author information

Author notes

  1. Lingna Deng and Qingxia Peng contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China

    Lingna Deng, Qingxia Peng, Hongxuan Wang, Jingrui Pan, Kuang Pan & Yidong Wang

  2. Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200433, China

    Ying Zhou

  3. Department of Orthopedic, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China

    Jinteng Li

  4. Center for Biotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China

    Yanfeng Wu

  5. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 107 Yan Jiang Road West, Guangzhou, 510120, China

    Yanfeng Wu & Yidong Wang

  6. Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    Yidong Wang

  7. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China

    Yidong Wang

Authors
  1. Lingna Deng
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  2. Qingxia Peng
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  7. Jinteng Li
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  8. Yanfeng Wu
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Corresponding authors

Correspondence to Yanfeng Wu or Yidong Wang.

Ethics declarations

Adverse events and compliance to protocol will be monitored by an independent data monitoring committee, with in-person monitoring visits and phone contacts. The study protocol and information consent forms have been approved by the Ethical Committee of the Sun Yat-sen Memorial Hospital, Sun Yat-sen University. The trial has been registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-INR-16008908; date of approval 25 July 2016). And all patients will be informed verbally and provided with a written document about the study by the investigators.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Significance Statement

This trial is the first to evaluate the safety, feasibility, and therapeutic mechanisms of allogenic BM-MSCs by intrathecal infusion in patients with severe cerebral infarction. This study protocol will provide a high level of evidence and better understanding of allogenic MSC therapy via intrathecal injection in patients with severe ischemic stroke.

Lingna Deng and Qingxia Peng are co-first authors.

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Deng, L., Peng, Q., Wang, H. et al. Intrathecal Injection of Allogenic Bone Marrow-Derived Mesenchymal Stromal Cells in Treatment of Patients with Severe Ischemic Stroke: Study Protocol for a Randomized Controlled Observer-Blinded Trial. Transl. Stroke Res. 10, 170–177 (2019). https://doi.org/10.1007/s12975-018-0634-y

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  • DOI: https://doi.org/10.1007/s12975-018-0634-y

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