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Trials
Published in: Trials 1/2013

Open Access 01-12-2013 | Study protocol

Intravenous transplantation of mesenchymal stem cells preconditioned with early phase stroke serum: current evidence and study protocol for a randomized trial

Authors: Suk Jae Kim, Gyeong Joon Moon, Won Hyuk Chang, Yun-Hee Kim, Oh Young Bang, For the STARTING-2 (STem cell Application Researches and Trials In NeuroloGy-2) collaborators

Published in: Trials | Issue 1/2013

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Abstract

Background

Recovery after a major stroke is usually limited, but cell therapy for patients with fixed neurologic deficits is emerging. Several recent clinical trials have investigated mesenchymal stem cell (MSC) therapy for patients with ischemic stroke. We previously reported the results of a controlled trial on the application of autologous MSCs in patients with ischemic stroke with a long-term follow-up of up to 5 years (the 'STem cell Application Researches and Trials In NeuroloGy’ (STARTING) study). The results from this pilot trial are challenging, but also raise important issues. In addition, there have been recent efforts to improve the safety and efficacy of MSC therapy for stroke.

Methods and design

The clinical and preclinical background and the STARTING-2 study protocol are provided. The trial is a prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial. Both acute and chronic stroke patients will be selected based on clinical and radiological features and followed for 3 months after MSC treatment. The subjects will be randomized into one of two groups: (A) a MSC group (n = 40) or (B) a control group (n = 20). Autologous MSCs will be intravenously administered after ex vivo culture expansion with autologous ischemic serum obtained as early as possible, to enhance the therapeutic efficacy (ischemic preconditioning). Objective outcome measurements will be performed using multimodal MRI and detailed functional assessments by blinded observers.

Discussion

This trial is the first to evaluate the efficacy of MSCs in patients with ischemic stroke. The results may provide better evidence for the effectiveness of MSC therapy in patients with ischemic stroke.

Trial registration

This trial was registered with ClinicalTrials.gov, number NCT01716481.
Appendix
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Literature
1.
Hong KS, Ali LK, Selco SL, Fonarow GC, Saver JL: Weighting components of composite end points in clinical trials: an approach using disability-adjusted life-years. Stroke. 2011, 42: 1722-1729. 10.1161/STROKEAHA.110.600106.CrossRefPubMedPubMedCentral
2.
Savitz SI, Dinsmore J, Wu J, Henderson GV, Stieg P, Caplan LR: Neurotransplantation of fetal porcine cells in patients with basal ganglia infarcts: a preliminary safety and feasibility study. Cerebrovasc Dis. 2005, 20: 101-107.CrossRefPubMed
3.
Sprigg N, Bath PM, Zhao L, Willmot MR, Gray LJ, Walker MF, Dennis MS, Russell N: 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, 37: 2979-2983. 10.1161/01.STR.0000248763.49831.c3.CrossRefPubMed
4.
Savitz SI, Misra V, Kasam M, Juneja H, Cox CS, Alderman S, Aisiku I, Kar S, Gee A, Grotta JC: Intravenous autologous bone marrow mononuclear cells for ischemic stroke. Ann Neurol. 2011, 70: 59-69. 10.1002/ana.22458.CrossRefPubMed
5.
Friedrich MA, Martins MP, Araujo MD, Klamt C, Vedolin L, Garicochea B, Raupp EF, Sartori E, Ammar J, Machado DC, Costa JC, Nogueira RG, Rosado-de-Castro PH, Mendez-Otero R, Freitas GR: 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 (Suppl 1): S13-S21.CrossRefPubMed
6.
Bang OY, Lee JS, Lee PH, Lee G: Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol. 2005, 57: 874-882. 10.1002/ana.20501.CrossRefPubMed
7.
Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY: A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells. 2010, 28: 1099-1106. 10.1002/stem.430.CrossRefPubMed
8.
Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S, Onodera R, Waxman SG, Kocsis JD: Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain. 2011, 134: 1790-1807. 10.1093/brain/awr063.CrossRefPubMedPubMedCentral
9.
Bhasin A, Srivastava MV, Kumaran SS, Mohanty S, Bhatia R, Bose S, Gaikwad S, Garg A, Airan B: Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra. 2011, 1: 93-104. 10.1159/000333381.CrossRefPubMedPubMedCentral
10.
Stem Cell Therapies as an Emerging Paradigm in Stroke Participants: 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: 510-515.CrossRef
11.
Dorman PJ, Sandercock PA: Considerations in the design of clinical trials of neuroprotective therapy in acute stroke. Stroke. 1996, 27: 1507-1515. 10.1161/01.STR.27.9.1507.CrossRefPubMed
12.
Lees JS, Sena ES, Egan KJ, Antonic A, Koblar SA, Howells DW, Macleod MR: Stem cell-based therapy for experimental stroke: a systematic review and meta-analysis. Int J Stroke. 2012, 7: 582-588. 10.1111/j.1747-4949.2012.00797.x.CrossRefPubMed
13.
Hermann DM, Chopp M: Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation. Lancet Neurol. 2012, 11: 369-380. 10.1016/S1474-4422(12)70039-X.CrossRefPubMedPubMedCentral
14.
Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L, Ho KL, Morshead C, Chopp M: Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab. 2004, 24: 441-448.CrossRefPubMed
15.
Kokaia Z, Thored P, Arvidsson A, Lindvall O: Regulation of stroke-induced neurogenesis in adult brain-recent scientific progress. Cereb Cortex. 2006, 16 (Suppl 1): i162-i167.CrossRefPubMed
16.
Darsalia V, Heldmann U, Lindvall O, Kokaia Z: Stroke-induced neurogenesis in aged brain. Stroke. 2005, 36: 1790-1795. 10.1161/01.STR.0000173151.36031.be.CrossRefPubMed
17.
Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O: Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002, 8: 963-970. 10.1038/nm747.CrossRefPubMed
18.
Li WY, Choi YJ, Lee PH, Huh K, Kang YM, Kim HS, Ahn YH, Lee G, Bang OY: Mesenchymal stem cells for ischemic stroke: changes in effects after ex vivo culturing. Cell Transplant. 2008, 17: 1045-1059. 10.3727/096368908786991551.CrossRefPubMed
19.
Yamashita T, Ninomiya M, Hernandez Acosta P, Garcia-Verdugo JM, Sunabori T, Sakaguchi M, Adachi K, Kojima T, Hirota Y, Kawase T, Araki N, Abe K, Okano H, Sawamoto K: Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. J Neurosci. 2006, 26: 6627-6636. 10.1523/JNEUROSCI.0149-06.2006.CrossRefPubMed
20.
Chopp M, Li Y: Treatment of neural injury with marrow stromal cells. Lancet Neurol. 2002, 1: 92-100. 10.1016/S1474-4422(02)00040-6.CrossRefPubMed
21.
Abrahams JM, Gokhan S, Flamm ES, Mehler MF: De novo neurogenesis and acute stroke: are exogenous stem cells really necessary?. Neurosurgery. 2004, 54: 150-155. 10.1227/01.NEU.0000097515.27930.5E.CrossRefPubMed
22.
Lindvall O, Kokaia Z: Recovery and rehabilitation in stroke: stem cells. Stroke. 2004, 35: 2691-2694. 10.1161/01.STR.0000143323.84008.f4.CrossRefPubMed
23.
Bang OY, Park HY, Yoon JH, Yeo SH, Kim JW, Lee MA, Park MH, Lee PH, Joo IS, Huh K: Predicting the long-term outcome after subacute stroke within the middle cerebral artery territory. J Clin Neurol. 2005, 1: 148-158. 10.3988/jcn.2005.1.2.148.CrossRefPubMedPubMedCentral
24.
Gilman S: Time course and outcome of recovery from stroke: relevance to stem cell treatment. Exp Neurol. 2006, 199: 37-41. 10.1016/j.expneurol.2005.12.003.CrossRefPubMed
25.
Hill WD, Hess DC, Martin-Studdard A, Carothers JJ, Zheng J, Hale D, Maeda M, Fagan SC, Carroll JE, Conway SJ: SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury. J Neuropathol Exp Neurol. 2004, 63: 84-96.CrossRefPubMed
26.
Shen LH, Li Y, Chen J, Zacharek A, Gao Q, Kapke A, Lu M, Raginski K, Vanguri P, Smith A, Chopp M: Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. J Cereb Blood Flow Metab. 2007, 27: 6-13. 10.1038/sj.jcbfm.9600311.CrossRefPubMed
27.
Misra V, Ritchie MM, Stone LL, Low WC, Janardhan V: Stem cell therapy in ischemic stroke: role of IV and intra-arterial therapy. Neurology. 2012, 79: S207-S212. 10.1212/WNL.0b013e31826959d2.CrossRefPubMedPubMedCentral
28.
Hess DC, Borlongan CV: Cell-based therapy in ischemic stroke. Expert Rev Neurother. 2008, 8: 1193-1201. 10.1586/14737175.8.8.1193.CrossRefPubMed
29.
Lloyd-Jones D, Adams R, Carnethon M, De Simone G, Ferguson TB, Flegal K, Ford E, Furie K, Go A, Greenlund K, Haase N, Hailpern S, Ho M, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott M, Meigs J, Mozaffarian D, Nichol G, O'Donnell C, Roger V, Rosamond W, Sacco R, Sorlie P, Stafford R, Steinberger J: Heart disease and stroke statistics - 2009 update: a report from the American heart association statistics committee and stroke statistics subcommittee. Circulation. 2009, 119: e21-e181.CrossRefPubMed
30.
Dihne M, Hartung HP, Seitz RJ: Restoring neuronal function after stroke by cell replacement: anatomic and functional considerations. Stroke. 2011, 42: 2342-2350. 10.1161/STROKEAHA.111.613422.CrossRefPubMed
31.
Kawai H, Yamashita T, Ohta Y, Deguchi K, Nagotani S, Zhang X, Ikeda Y, Matsuura T, Abe K: Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. J Cereb Blood Flow Metab. 2010, 30: 1487-1493. 10.1038/jcbfm.2010.32.CrossRefPubMedPubMedCentral
32.
Savitz SI, Chopp M, Deans R, Carmichael ST, Phinney D, Wechsler L: Stem cell therapy as an emerging paradigm for stroke (STEPS) II. Stroke. 2011, 42: 825-829.CrossRefPubMed
33.
Wechsler LR: Clinical trials of stroke therapy: which cells, which patients?. Stroke. 2009, 40: S149-S151. 10.1161/STROKEAHA.108.533208.CrossRefPubMed
34.
Halme DG, Kessler DA: FDA regulation of stem-cell-based therapies. N Engl J Med. 2006, 355: 1730-1735. 10.1056/NEJMhpr063086.CrossRefPubMed
35.
36.
37.
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. 2008, 83: 723-730. 10.1038/sj.clpt.6100386.CrossRefPubMed
38.
Spees JL, Gregory CA, Singh H, Tucker HA, Peister A, Lynch PJ, Hsu SC, Smith J, Prockop DJ: Internalized antigens must be removed to prepare hypoimmunogenic mesenchymal stem cells for cell and gene therapy. Mol Ther. 2004, 9: 747-756. 10.1016/j.ymthe.2004.02.012.CrossRefPubMed
39.
Mannello F, Tonti GA: Concise review: no breakthroughs for human mesenchymal and embryonic stem cell culture: conditioned medium, feeder layer, or feeder-free; medium with fetal calf serum, human serum, or enriched plasma; serum-free, serum replacement nonconditioned medium, or ad hoc formula? All that glitters is not gold!. Stem Cells. 2007, 25: 1603-1609. 10.1634/stemcells.2007-0127.CrossRefPubMed
40.
Boncoraglio GB, Bersano A, Candelise L, Reynolds BA, Parati EA: Stem cell transplantation for ischemic stroke. Cochrane Database Syst Rev. 2010, 9: CD007231-PubMed
41.
Grayson WL, Zhao F, Bunnell B, Ma T: Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells. Biochem Biophys Res Commun. 2007, 358: 948-953. 10.1016/j.bbrc.2007.05.054.CrossRefPubMed
42.
Pasha Z, Wang Y, Sheikh R, Zhang D, Zhao T, Ashraf M: Preconditioning enhances cell survival and differentiation of stem cells during transplantation in infarcted myocardium. Cardiovasc Res. 2008, 77: 134-142.CrossRefPubMed
43.
Borlongan CV, Hadman M, Sanberg CD, Sanberg PR: Central nervous system entry of peripherally injected umbilical cord blood cells is not required for neuroprotection in stroke. Stroke. 2004, 35: 2385-2389. 10.1161/01.STR.0000141680.49960.d7.CrossRefPubMed
44.
van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ: Regeneration of the ischemic brain by engineered stem cells: fuelling endogenous repair processes. Brain Res Rev. 2009, 61: 1-13. 10.1016/j.brainresrev.2009.03.003.CrossRefPubMed
45.
Bang OY, Jin KS, Hwang MN, Kang HY, Kim BJ, Lee SJ, Kang S, Hwang YK, Ahn JS, Sung KW: The effect of CXCR4 overexpression on mesenchymal stem cell transplantation in ischemic stroke. Cell Med. 2012, 4: 65-76. 10.3727/215517912X647172.CrossRefPubMedPubMedCentral
46.
Schaller B, Graf R: Cerebral ischemic preconditioning. An experimental phenomenon or a clinical important entity of stroke prevention?. J Neurol. 2002, 249: 1503-1511. 10.1007/s00415-002-0933-8.CrossRefPubMed
47.
Maulik N, Yoshida T, Engelman RM, Deaton D, Flack JE, Rousou JA, Das DK: Ischemic preconditioning attenuates apoptotic cell death associated with ischemia/reperfusion. Mol Cell Biochem. 1998, 186: 139-145. 10.1023/A:1006883717174.CrossRefPubMed
48.
Wegener S, Gottschalk B, Jovanovic V, Knab R, Fiebach JB, Schellinger PD, Kucinski T, Jungehulsing GJ, Brunecker P, Muller B, Banasik A, Amberger N, Wernecke KD, Siebler M, Rother J, Villringer A, Weih M: Transient ischemic attacks before ischemic stroke: preconditioning the human brain? A multicenter magnetic resonance imaging study. Stroke. 2004, 35: 616-621. 10.1161/01.STR.0000115767.17923.6A.CrossRefPubMed
49.
Haider H, Ashraf M: Strategies to promote donor cell survival: combining preconditioning approach with stem cell transplantation. J Mol Cell Cardiol. 2008, 45: 554-566. 10.1016/j.yjmcc.2008.05.004.CrossRefPubMedPubMedCentral
50.
Kohin S, Stary CM, Howlett RA, Hogan MC: Preconditioning improves function and recovery of single muscle fibers during severe hypoxia and reoxygenation. Am J Physiol Cell Physiol. 2001, 281: C142-C146.PubMed
51.
Werner M, Mayleben T, Van Bokkelen G: Autologous cell therapies: the importance of regulatory oversight. Regen Med. 2012, 7: 100-103. 10.2217/rme.12.90.CrossRefPubMed
52.
Zacharek A, Shehadah A, Chen J, Cui X, Roberts C, Lu M, Chopp M: Comparison of bone marrow stromal cells derived from stroke and normal rats for stroke treatment. Stroke. 2010, 41: 524-530. 10.1161/STROKEAHA.109.568881.CrossRefPubMedPubMedCentral
53.
Bliss T, Guzman R, Daadi M, Steinberg GK: Cell transplantation therapy for stroke. Stroke. 2007, 38: 817-826. 10.1161/01.STR.0000247888.25985.62.CrossRefPubMed
54.
Saver JL, Gornbein J: Treatment effects for which shift or binary analyses are advantageous in acute stroke trials. Neurology. 2009, 72: 1310-1315. 10.1212/01.wnl.0000341308.73506.b7.CrossRefPubMedPubMedCentral
55.
Lees KR, Bath PM, Schellinger PD, Kerr DM, Fulton R, Hacke W, Matchar D, Sehra R, Toni D: Contemporary outcome measures in acute stroke research: choice of primary outcome measure. Stroke. 2012, 43: 1163-1170. 10.1161/STROKEAHA.111.641423.CrossRefPubMed
56.
Demeurisse G, Demol O, Robaye E: Motor evaluation in vascular hemiplegia. Eur Neurol. 1980, 19: 382-389. 10.1159/000115178.CrossRefPubMed
57.
Berglund K, Fugl-Meyer AR: Upper extremity function in hemiplegia. A cross-validation study of two assessment methods. Scand J Rehabil Med. 1986, 18: 155-157.PubMed
58.
Mathiowetz V, Wiemer DM, Federman SM: Grip and pinch strength: norms for 6- to 19-year-olds. Am J Occup Ther. 1986, 40: 705-711. 10.5014/ajot.40.10.705.CrossRefPubMed
59.
Desrosiers J, Bravo G, Hebert R, Dutil E, Mercier L: Validation of the box and block test as a measure of dexterity of elderly people: reliability, validity, and norms studies. Arch Phys Med Rehabil. 1994, 75: 751-755.PubMed
60.
Collen FM, Wade DT, Bradshaw CM: Mobility after stroke: reliability of measures of impairment and disability. Int Disabil Stud. 1990, 12: 6-9. 10.3109/03790799009166594.CrossRefPubMed
61.
Cheeran B, Talelli P, Mori F, Koch G, Suppa A, Edwards M, Houlden H, Bhatia K, Greenwood R, Rothwell JC: A common polymorphism in the brain-derived neurotrophic factor gene (BDNF) modulates human cortical plasticity and the response to rTMS. J Physiol. 2008, 586: 5717-5725. 10.1113/jphysiol.2008.159905.CrossRefPubMedPubMedCentral
62.
Siironen J, Juvela S, Kanarek K, Vilkki J, Hernesniemi J, Lappalainen J: The Met allele of the BDNF Val66Met polymorphism predicts poor outcome among survivors of aneurysmal subarachnoid hemorrhage. Stroke. 2007, 38: 2858-2860. 10.1161/STROKEAHA.107.485441.CrossRefPubMed
63.
Vilkki J, Lappalainen J, Juvela S, Kanarek K, Hernesniemi JA, Siironen J: Relationship of the Met allele of the brain-derived neurotrophic factor Val66Met polymorphism to memory after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2008, 63: 198-203. 10.1227/01.NEU.0000320382.21577.8E.CrossRefPubMed
64.
Kim SJ, Moon GJ, Cho YH, Kang HY, Hyung NK, Kim D, Lee JH, Nam JY, Bang OY: Circulating mesenchymal stem cells microparticles in patients with cerebrovascular disease. PLoS ONE. 2012, 7: e37036-10.1371/journal.pone.0037036.CrossRefPubMedPubMedCentral
65.
Cheung K, Kaufmann P: Efficiency perspectives on adaptive designs in stroke clinical trials. Stroke. 2011, 42: 2990-2994. 10.1161/STROKEAHA.111.620765.CrossRefPubMedPubMedCentral
Metadata
Title
Intravenous transplantation of mesenchymal stem cells preconditioned with early phase stroke serum: current evidence and study protocol for a randomized trial
Authors
Suk Jae Kim
Gyeong Joon Moon
Won Hyuk Chang
Yun-Hee Kim
Oh Young Bang
For the STARTING-2 (STem cell Application Researches and Trials In NeuroloGy-2) collaborators
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Trials / Issue 1/2013
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/1745-6215-14-317

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