A Phase III Clinical Trial Showing Limited Efficacy of Autologous Mesenchymal Stem Cell Therapy for Spinal Cord Injury

Neurosurgery

Volumn 78, Issue 3, 2016, Pages 436-447

  Oh, Sun Kyu ^a   Choi, Kyoung Hyo ^b   Yoo, Jong Yoon ^b   Kim, Dae Yul ^b   Kim, Sang Joon ^a   Jeon, Sang Ryong ^a  

^a University of Ulsan College of Medicine   (South Korea)

^b Department of Rehabilitation Medicine ^*  (South Korea)

Author keywords

Clinical trial; Diffusion tensor imaging; Electrophysiological study; Intramedullary injection; Mesenchymal stem cells; Spinal cord injury

Indexed keywords

ADULT; AGED; ARTICLE; BRAIN ELECTROPHYSIOLOGY; CERVICAL SPINE FRACTURE; CLINICAL ARTICLE; DIFFUSION TENSOR IMAGING; EVOKED MUSCLE RESPONSE; EVOKED SOMATOSENSORY RESPONSE; FEMALE; FOLLOW UP; FUNCTIONAL ELECTRICAL STIMULATION; HUMAN; LIGAMENT CALCINOSIS; MALE; MESENCHYMAL STEM CELL TRANSPLANTATION; MIDDLE AGED; NEUROLOGIC EXAMINATION; NUCLEAR MAGNETIC RESONANCE IMAGING; PERONEUS NERVE; PHASE 3 CLINICAL TRIAL; PRIORITY JOURNAL; SPINAL CORD INJURY; ULNAR NERVE; AUTOLOGOUS STEM CELL TRANSPLANTATION; CERVICAL SPINE DISLOCATION; CLINICAL EFFECTIVENESS; DURA MATER; ELECTROPHYSIOLOGY; LATENT PERIOD; MOTOR EVOKED POTENTIAL; MUSCLE RIGIDITY; PATIENT SAFETY; RADIAL NERVE; SOMATOSENSORY EVOKED POTENTIAL; THERAPY EFFECT; AUTOTRANSPLANTATION; CLINICAL TRIAL; CONVALESCENCE; CYTOLOGY; MESENCHYMAL STROMA CELL; PROCEDURES; SPINAL CORD INJURIES;

ADULT; DIFFUSION TENSOR IMAGING; FEMALE; HUMANS; MAGNETIC RESONANCE IMAGING; MALE; MESENCHYMAL STEM CELL TRANSPLANTATION; MESENCHYMAL STROMAL CELLS; MIDDLE AGED; RECOVERY OF FUNCTION; SPINAL CORD INJURIES; TRANSPLANTATION, AUTOLOGOUS;

EID: 84959178600     PISSN: 0148396X     EISSN: 15244040     Source Type: Journal    
DOI: 10.1227/NEU.0000000000001056     Document Type: Article

References (57)

1. Branco F, Cardenas DD, Svircev JN. Spinal cord injury: a comprehensive review. Phys Med Rehabil Clin N Am. 2007;18(4):651-679, v.
2. Polinder S, Meerding WJ, Mulder S, Petridou E, van Beeck E. Assessing the burden of injury in six European countries. Bull World Health Organ. 2007;85(1): 27-34.
3. Yiu G, He Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci. 2006;7 (8):617-627.
4. Lindvall O, Kokaia Z. Stem cells for the treatment of neurological disorders. Nature. 2006;441(7097):1094-1096.
5. Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med. 2010;5 (6):933-946.
6. Kim SU, De Vellis J. Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res. 2009;87(10):2183-2200.
7. Kishk NA, Gabr H, Hamdy S, et al. Case control series of intrathecal autologous bone marrow mesenchymal stem cell therapy for chronic spinal cord injury. Neurorehabil Neural Repair. 2010;24(8):702-708.
8. Saberi H, Firouzi M, Habibi Z, et al. Safety of intramedullary Schwann cell transplantation for postrehabilitation spinal cord injuries: 2-year follow-up of 33 cases: clinical article. J Neurosurg Spine. 2011;15(5):515-525.
9. Mackay-Sim A, Feron F, Cochrane J, et al. Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain. 2008;131(9): 2376-2386.
10. Ronaghi M, Erceg S, Moreno-Manzano V, Stojkovic M. Challenges of stem cell therapy for spinal cord injury: human embryonic stem cells, endogenous neural stem cells, or induced pluripotent stem cells? Stem Cells. 2010;28(1): 93-99.
11. Mothe AJ, Tator CH. Review of transplantation of neural stem/progenitor cells for spinal cord injury. Int J Dev Neurosci. 2013;31(7):701-713.
12. Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol. 2009;217 (2):318-324.
13. Hofstetter CP, Schwarz EJ, Hess D, et al. Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci USA. 2002;99(4):2199-2204.
14. Neirinckx V, Cantinieaux D, Coste C, Rogister B, Franzen R, Wislet-Gendebien S. Concise review: spinal cord injuries: how could adult mesenchymal and neural crest stem cells take up the challenge? Stem Cells. 2014;32(4):829-843.
15. Park JH, Kim DY, Sung IY, et al. Long-term results of spinal cord injury therapy using mesenchymal stem cells derived from bone marrow in humans. Neurosurgery. 2012;70(5):1238-1247.
16. Suh HI, Min J, Choi KH, Kim SW, Kim KS, Jeon SR. Axonal regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats. Acta Neurochir (Wien). 2011;153(5):1003-1010.
17. Abrams MB, Dominguez C, Pernold K, et al. Multipotent mesenchymal stromal cells attenuate chronic inflammation and injury-induced sensitivity to mechanical stimuli in experimental spinal cord injury. Restor Neurol Neurosci. 2008;27(4):307-321.
18. Neuhuber B, Himes BT, Shumsky JS, Gallo G, Fischer I. Axon growth and recovery of function supported by human bone marrow stromal cells in the injured spinal cord exhibit donor variations. Brain Res. 2005;1035(1):73-85.
19. Yoon SH, Shim YS, Park YH, et al. Complete spinal cord injury treatment using autologous bone marrow cell transplantation and bone marrow stimulation with granulocyte Macrophage-Colony stimulating factor: phase I/II clinical trial. Stem Cells. 2007;25(8):2066-2073.
20. Wright KT, Masri WE, Osman A, Chowdhury J, Johnson WE. Concise review: bone marrow for the treatment of spinal cord injury: mechanisms and clinical applications. Stem Cells. 2011;29(2):169-178.
21. Jiang PC, Xiong WP, Wang G, et al. A clinical trial report of autologous bone marrow-derived mesenchymal stem cell transplantation in patients with spinal cord injury. Exp Ther Med. 2013;6(1):140-146.
22. Karamouzian S, Nematollahi-Mahani SN, Nakhaee N, Eskandary H. Clinical safety and primary efficacy of bone marrow mesenchymal cell transplantation in subacute spinal cord injured patients. Clin Neurol Neurosurg. 2012;114(7): 935-939.
23. Kirshblum S, Waring W. Updates for the International Standards for neurological classification of spinal cord injury. Phys Med Rehabil Clin N Am. 2014;25(3):505-517.
24. Kumar AA, Kumar SR, Narayanan R, Arul K, Baskaran M. Autologous bone marrow derived mononuclear cell therapy for spinal cord injury: a phase I/II clinical safety and primary efficacy data. Exp Clin Transpl. 2009;7(4):241-248.
25. Syková E, Homola A, Mazanec R, et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transpl. 2006;15(8-9):675-687.
26. Moviglia G, Fernandez Vina R, Brizuela J, et al. Combined protocol of cell therapy for chronic spinal cord injury. Report on the electrical and functional recovery of two patients. Cytotherapy. 2006;8(3):202-209.
27. Paul C, Samdani AF, Betz RR, Fischer I, Neuhuber B. Grafting of human bone marrow stromal cells into spinal cord injury: a comparison of delivery methods. Spine (Phila Pa 1976). 2009;34(4):328.
28. Bakshi A, Hunter C, Swanger S, Lepore A, Fischer I. Minimally invasive delivery of stem cells for spinal cord injury: advantages of the lumbar puncture technique. J Neurosurg Spine. 2004;1(3):330-337.
29. McColgan P, Sharma P, Bentley P. Stem cell tracking in human trials: a meta-regression. Stem Cell Rev. 2011;7(4):1031-1040.
30. Deng YB, Liu XG, Liu ZG, Liu XL, Liu Y, Zhou GQ. Implantation of BM mesenchymal stem cells into injured spinal cord elicits de novo neurogenesis and functional recovery: evidence from a study in rhesus monkeys. Cytotherapy. 2006;8 (3):210-214.
31. Guo JS, Zeng YS, Li HB, et al. Cotransplant of neural stem cells and NT-3 gene modified Schwann cells promote the recovery of transected spinal cord injury. Spinal Cord. 2007;45(1):15-24.
32. Nori S, Okada Y, Yasuda A, et al. Grafted human-induced pluripotent stem-cell-derived neurospheres promote motor functional recovery after spinal cord injury in mice. Proc Natl Acad Sci USA. 2011;108(40):16825-16830.
33. Ryu HH, Lim JH, Byeon YE, et al. Functional recovery and neural differentiation after transplantation of allogenic adipose-derived stem cells in a canine model of acute spinal cord injury. J Vet Sci. 2009;10(4):273-284.
34. Curt A, Schwab M, Dietz V. Providing the clinical basis for new interventional therapies: refined diagnosis and assessment of recovery after spinal cord injury. Spinal Cord. 2004;42(1):1-6.
35. Kirshblum SC, O'Connor KC. Predicting neurologic recovery in traumatic cervical spinal cord injury. Arch Phys Med Rehabil. 1998;79(11):1456-1466.
36. Tator CH. Review of treatment trials in human spinal cord injury: issues, difficulties, and recommendations. Neurosurgery. 2006;59(5):957-987.
37. Knoller N, Auerbach G, Fulga V, et al. Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine. 2005;3(3):173-181.
38. Lima C, Escada P, Pratas-Vital J, et al. Olfactory mucosal autografts and rehabilitation for chronic traumatic spinal cord injury. Neurorehabil Neural Repair. 2010;24(1):10-22.
39. Le Bihan D, Mangin JF, Poupon C, et al. Diffusion tensor imaging: concepts and applications. J Magn Reson Imaging. 2001;13(4):534-546.
40. Kara B, Celik A, Karadereler S, et al. The role of DTI in early detection of cervical spondylotic myelopathy: a preliminary study with 3-T MRI. Neuroradiology. 2011; 53(8):609-616.
41. Chang Y, Jung T-D, Yoo DS, Hyun JK. Diffusion tensor imaging and fiber tractography of patients with cervical spinal cord injury. J Neurotrauma. 2010;27 (11):2033-2040.
42. Ellingson B, Ulmer J, Kurpad S, Schmit B. Diffusion tensor MR imaging in chronic spinal cord injury. AJNR Am J Neuroradiol. 2008;29(10):1976-1982.
43. Kamble RB, Venkataramana NK, Naik AL, Rao SV. Diffusion tensor imaging in spinal cord injury. Indian J Radiol Imaging. 2011;21(3):221-224.
44. Rajasekaran S, Kanna R, Shetty A. Diffusion tensor imaging of the spinal cord and its clinical applications. J Bone Joint Surg Br. 2012;94(8):1024-1031.
45. Vargas MI, Delavelle J, Jlassi H, et al. Clinical applications of diffusion tensor tractography of the spinal cord. Neuroradiology. 2008;50(1):25-29.
46. Bunge MB. Novel combination strategies to repair the injured mammalian spinal cord. J Spinal Cord Med. 2008;31(3):262.
47. Chen A, Xu XM, Kleitman N, Bunge MB. Methylprednisolone administration improves axonal regeneration into Schwann cell grafts in transected adult rat thoracic spinal cord. Exp Neurol. 1996;138(2):261-276.
48. Xu XM, Guénard V, Kleitman N, Aebischer P, Bunge MB. A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol. 1995;134(2):261-272.
49. Shin DA, Pennant WA, Yoon DH, Ha Y, Kim KN. Co-transplantation of bone marrow-derived mesenchymal stem cells and nanospheres containing FGF-2 improve cell survival and neurological function in the injured rat spinal cord. Acta Neurochir (Wien). 2014;156(2):297-303.
50. Hall ED, Springer JE. Neuroprotection and acute spinal cord injury: a reappraisal. NeuroRx. 2004;1(1):80-100.
51. Tator CH, Fehlings MG. Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms. J Neurosurg. 1991;75(1):15-26.
52. Houle JD, Tessler A. Repair of chronic spinal cord injury. Exp Neurol. 2003;182 (2):247-260.
53. Tobias CA, Han SS, Shumsky JS, et al. Alginate encapsulated BDNF-producing fibroblast grafts permit recovery of function after spinal cord injury in the absence of immune suppression. J Neurotrauma. 2005;22(1):138-156.
54. Storer PD, Houle JD. betaII-tubulin and GAP 43 mRNA expression in chronically injured neurons of the red nucleus after a second spinal cord injury. Exp Neurol. 2003;183(2):537-547.
55. Kobayashi NR, Fan DP, Giehl KM, Bedard AM, Wiegand SJ, Tetzlaff W. BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and talpha1-tubulin mRNA expression, and promote axonal regeneration. J Neurosci. 1997;17(24):9583-9595.
56. Zieker D, Schafer R, Glatzle J, et al. Lactate modulates gene expression in human mesenchymal stem cells. Langenbecks Arch Surg. 2008;393(3):297-301.
57. Yagi H, Soto-Gutierrez A, Parekkadan B, et al. Mesenchymal stem cells: mechanisms of immunomodulation and homing. Cell Transpl. 2010;19(6): 667-679.