nach oben

Erschienen in:

16.05.2019 | Review Article

Stem cell/cellular interventions in human spinal cord injury: Is it time to move from guidelines to regulations and legislations? Literature review and Spinal Cord Society position statement

verfasst von: Harvinder S. Chhabra, Kanchan Sarda, Geeta Jotwani, M. Gourie-Devi, Erkan Kaptanoglu, Susan Charlifue, S. L. Yadav, B. Mohapatra, Abhishek Srivastava, Kedar Phadke

Erschienen in: European Spine Journal | Ausgabe 8/2019

Einloggen, um Zugang zu erhalten

Abstract

Purpose

In preclinical studies, many stem cell/cellular interventions demonstrated robust regeneration and/or repair in case of SCI and were considered a promising therapeutic candidate. However, data from clinical studies are not robust. Despite lack of substantial evidence for the efficacy of these interventions in spinal cord injury (SCI), many clinics around the world offer them as “therapy.” These “clinics” claim efficacy through patient testimonials and self-advertisement without any scientific evidence to validate their claims. Thus, SCS established a panel of experts to review published preclinical studies, clinical studies and current global guidelines/regulations on usage of cellular transplants and make recommendations for their clinical use.

Methods

The literature review and draft position statement was compiled and circulated among the panel and relevant suggestions incorporated to reach consensus. This was discussed and finalized in an open forum during the SCS Annual Meeting, ISSICON.

Results

Preclinical evidence suggests safety and clinical potency of cellular interventions after SCI. However, evidence from clinical studies consisted of mostly case reports or uncontrolled case series/studies. Data from animal studies cannot be generalized to human SCI with regard to toxicity prediction after auto/allograft transplantation.

Conclusions

Currently, cellular/stem cell transplantation for human SCI is experimental and needs to be tested through a valid clinical trial program. It is not ethical to provide unproven transplantation as therapy with commercial implications. To stop the malpractice of marketing such “unproven therapies” to a vulnerable population, it is crucial that all countries unite to form common, well-defined regulations/legislation on their use in SCI.

Graphical abstract

These slides can be retrieved from Electronic Supplementary Material.

Nur mit Berechtigung zugänglich

Sarda K, Chhabra HS (2015) Cellular transplantation for human spinal cord injury: an overview. In: Chhabra HS (ed) ISCoS textbook on comprehensive management of spinal cord injury, first edit. Wolters Kluwer(India)Pvt. Ltd., New Delhi, pp 1048–1058

Falanga V (2012) Stem cells in tissue repair and regeneration. J Investig Dermatol 132:1538–1541. https://doi.org/10.1038/jid.2012.77 CrossRefPubMed

Hyun I (2010) The bioethics of stem cell research and therapy. J Clin Investig 120:71–75. https://doi.org/10.1172/JCI40435 CrossRefPubMedPubMedCentral

Chhabra HS, Sarda K (2015) Stem cell therapy in spinal trauma: does it have scientific validity? Indian J Orthop 49:56–71. https://doi.org/10.4103/0019-5413.143913 CrossRefPubMedPubMedCentral

Can A (2008) A concise review on the classification and nomenclature of stem cells. Turk J Hematol 25:57–59

Prokhorova TA, Harkness LM, Frandsen U et al (2009) Teratoma formation by human embryonic stem cells is site dependent and enhanced by the presence of Matrigel. Stem Cells Dev 18:47–54. https://doi.org/10.1089/scd.2007.0266 CrossRefPubMed

Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147CrossRefPubMed

Li J, Lepski G (2013) Cell transplantation for spinal cord injury: a systematic review. Biomed Res Int 2013:786475. https://doi.org/10.1155/2013/786475 CrossRefPubMedPubMedCentral

Mezey E, Key S, Vogelsang G et al (2003) Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci USA 100:1364–1369. https://doi.org/10.1073/pnas.0336479100 CrossRefPubMedPubMedCentral

10.

Brazelton TR, Rossi FM, Keshet GI, Blau HM (2000) From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290:1775–1779CrossRefPubMed

11.

Mariano ED, Batista CM, Barbosa BJAP et al (2014) Current perspectives in stem cell therapy for spinal cord repair in humans: a review of work from the past 10 years. Arq Neuropsiquiatr 72:451–456CrossRefPubMed

12.

Carrade DD, Affolter VK, Outerbridge CA et al (2011) Intradermal injections of equine allogeneic umbilical cord-derived mesenchymal stem cells are well tolerated and do not elicit immediate or delayed hypersensitivity reactions. Cytotherapy 13:1180–1192. https://doi.org/10.3109/14653249.2011.602338 CrossRefPubMed

13.

Sarda K, Chhabra HS (2015) Spinal cord injury research: targets for repair. In: Chhabra HS (ed) ISCoS textbook on comprehensive management of spinal cord injury, first. Wolters Kluwer(India)Pvt. Ltd., New Delhi, pp 1025–1039

14.

Yiu G, He Z (2006) Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7:617–627. https://doi.org/10.1038/nrn1956 CrossRefPubMedPubMedCentral

15.

Zurita M, Otero L, Aguayo C et al (2010) Cell therapy for spinal cord repair: optimization of biologic scaffolds for survival and neural differentiation of human bone marrow stromal cells. Cytotherapy 12:522–537. https://doi.org/10.3109/14653241003615164 CrossRefPubMed

16.

Chhabra HS, Sarda K (2017) Clinical translation of stem cell based interventions for spinal cord injury—are we there yet? Adv Drug Deliv Rev. https://doi.org/10.1016/j.addr.2017.09.021 CrossRefPubMed

17.

Salazar DL, Uchida N, Hamers FPT et al (2010) Human neural stem cells differentiate and promote locomotor recovery in an early chronic spinal cord injury NOD-scid mouse model. PLoS ONE 5:e12272. https://doi.org/10.1371/journal.pone.0012272 CrossRefPubMedPubMedCentral

18.

Okano H, Ogawa Y, Nakamura M et al (2003) Transplantation of neural stem cells into the spinal cord after injury. Semin Cell Dev Biol 14:191–198CrossRefPubMed

19.

Ziegler MD, Hsu D, Takeoka A et al (2011) Further evidence of olfactory ensheathing glia facilitating axonal regeneration after a complete spinal cord transection. Exp Neurol 229:109–119. https://doi.org/10.1016/j.expneurol.2011.01.007 CrossRefPubMedPubMedCentral

20.

Ramón-Cueto A, Avila J (1998) Olfactory ensheathing glia: properties and function. Brain Res Bull 46:175–187CrossRefPubMed

21.

Imaizumi T, Lankford KL, Waxman SG et al (1998) Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. J Neurosci 18:6176–6185CrossRefPubMedPubMedCentral

22.

Kato T, Honmou O, Uede T et al (2000) Transplantation of human olfactory ensheathing cells elicits remyelination of demyelinated rat spinal cord. Glia 30:209–218CrossRefPubMedPubMedCentral

23.

Ramón-Cueto A, Cordero MI, Santos-Benito FF, Avila J (2000) Functional recovery of paraplegic rats and motor axon regeneration in their spinal cords by olfactory ensheathing glia. Neuron 25:425–435CrossRefPubMed

24.

Raisman G, Barnett SC, Ramón-Cueto A (2012) Repair of central nervous system lesions by transplantation of olfactory ensheathing cells. Handb Clin Neurol 109:541–549. https://doi.org/10.1016/B978-0-444-52137-8.00033-4 CrossRefPubMed

25.

Toft A, Scott DT, Barnett SC, Riddell JS (2007) Electrophysiological evidence that olfactory cell transplants improve function after spinal cord injury. Brain 130:970–984. https://doi.org/10.1093/brain/awm040 CrossRefPubMed

26.

Barnett SC, Alexander CL, Iwashita Y et al (2000) Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons. Brain 123(Pt 8):1581–1588CrossRefPubMed

27.

Ramón-Cueto A, Plant GW, Avila J, Bunge MB (1998) Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J Neurosci 18:3803–3815CrossRefPubMedPubMedCentral

28.

Lu J, Féron F, Ho SM et al (2001) Transplantation of nasal olfactory tissue promotes partial recovery in paraplegic adult rats. Brain Res 889:344–357CrossRefPubMed

29.

Weidner N, Blesch A, Grill RJ, Tuszynski MH (1999) Nerve growth factor-hypersecreting Schwann cell grafts augment and guide spinal cord axonal growth and remyelinate central nervous system axons in a phenotypically appropriate manner that correlates with expression of L1. J Comp Neurol 413:495–506CrossRefPubMed

30.

Park H-W, Lim M-J, Jung H et al (2010) Human mesenchymal stem cell-derived Schwann cell-like cells exhibit neurotrophic effects, via distinct growth factor production, in a model of spinal cord injury. Glia 58:1118–1132. https://doi.org/10.1002/glia.20992 CrossRefPubMed

31.

Xu Y, Liu Z, Liu L et al (2008) Neurospheres from rat adipose-derived stem cells could be induced into functional Schwann cell-like cells in vitro. BMC Neurosci 9:21. https://doi.org/10.1186/1471-2202-9-21 CrossRefPubMedPubMedCentral

32.

Biernaskie JA, McKenzie IA, Toma JG, Miller FD (2006) Isolation of skin-derived precursors (SKPs) and differentiation and enrichment of their Schwann cell progeny. Nat Protoc 1:2803–2812. https://doi.org/10.1038/nprot.2006.422 CrossRefPubMed

33.

Xu XM, Chen A, Guénard V et al (1997) Bridging Schwann cell transplants promote axonal regeneration from both the rostral and caudal stumps of transected adult rat spinal cord. J Neurocytol 26:1–16CrossRefPubMed

34.

Kanno H, Pressman Y, Moody A et al (2014) Combination of engineered Schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. J Neurosci 34:1838–1855. https://doi.org/10.1523/JNEUROSCI.2661-13.2014 CrossRefPubMedPubMedCentral

35.

Saberi H, Moshayedi P, Aghayan H-R et al (2008) Treatment of chronic thoracic spinal cord injury patients with autologous Schwann cell transplantation: an interim report on safety considerations and possible outcomes. Neurosci Lett 443:46–50. https://doi.org/10.1016/j.neulet.2008.07.041 CrossRefPubMed

36.

Yazdani SO, Hafizi M, Zali A-R et al (2013) Safety and possible outcome assessment of autologous Schwann cell and bone marrow mesenchymal stromal cell co-transplantation for treatment of patients with chronic spinal cord injury. Cytotherapy 15:782–791. https://doi.org/10.1016/j.jcyt.2013.03.012 CrossRefPubMed

37.

Lima C, Pratas-Vital J, Escada P et al (2006) Olfactory mucosa autografts in human spinal cord injury: a pilot clinical study. J Spinal Cord Med 29:191–203 (discussion 204–6) CrossRefPubMedPubMedCentral

38.

Mackay-Sim A, Féron F, Cochrane J et al (2008) Autologous olfactory ensheathing cell transplantation in human paraplegia: a 3-year clinical trial. Brain 131:2376–2386. https://doi.org/10.1093/brain/awn173 CrossRefPubMedPubMedCentral

39.

Chhabra HS, Lima C, Sachdeva S et al (2009) Autologous olfactory [corrected] mucosal transplant in chronic spinal cord injury: an Indian Pilot Study. Spinal Cord 47:887–895. https://doi.org/10.1038/sc.2009.54 CrossRefPubMed

40.

Zhou X-H, Ning G-Z, Feng S-Q et al (2012) Transplantation of autologous activated Schwann cells in the treatment of spinal cord injury: six cases, more than five years of follow-up. Cell Transplant 21(Suppl 1):S39–S47. https://doi.org/10.3727/096368912X633752 CrossRefPubMed

41.

Prewitt CM, Niesman IR, Kane CJ, Houlé JD (1997) Activated macrophage/microglial cells can promote the regeneration of sensory axons into the injured spinal cord. Exp Neurol 148:433–443. https://doi.org/10.1006/exnr.1997.6694 CrossRefPubMed

42.

Pedram MS, Dehghan MM, Soleimani M et al (2010) Transplantation of a combination of autologous neural differentiated and undifferentiated mesenchymal stem cells into injured spinal cord of rats. Spinal Cord 48:457–463. https://doi.org/10.1038/sc.2009.153 CrossRefPubMed

43.

Tarasenko YI, Gao J, Nie L et al (2007) Human fetal neural stem cells grafted into contusion-injured rat spinal cords improve behavior. J Neurosci Res 85:47–57. https://doi.org/10.1002/jnr.21098 CrossRefPubMed

44.

Shin JC, Kim KN, Yoo J et al (2015) Clinical trial of human fetal brain-derived neural stem/progenitor cell transplantation in patients with traumatic cervical spinal cord injury. Neural Plast 2015:630932. https://doi.org/10.1155/2015/630932 CrossRefPubMedPubMedCentral

45.

Bretzner F, Gilbert F, Baylis F, Brownstone RM (2011) Target populations for first-in-human embryonic stem cell research in spinal cord injury. Cell Stem Cell 8:468–475. https://doi.org/10.1016/j.stem.2011.04.012 CrossRefPubMed

46.

Deb KD, Sarda K (2008) Human embryonic stem cells: preclinical perspectives. J Transl Med 6:7CrossRefPubMedPubMedCentral

47.

Lebkowski J (2011) GRNOPC1: the world’s first embryonic stem cell-derived therapy. Interview with Jane Lebkowski. Regen Med 6:11–13. https://doi.org/10.2217/rme.11.77 CrossRefPubMed

48.

Liras A (2010) Future research and therapeutic applications of human stem cells: general, regulatory, and bioethical aspects. J Transl Med 8:131. https://doi.org/10.1186/1479-5876-8-131 CrossRefPubMedPubMedCentral

49.

Knoller N, Auerbach G, Fulga V et al (2005) Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: phase I study results. J Neurosurg Spine 3:173–181. https://doi.org/10.3171/spi.2005.3.3.0173 CrossRefPubMed

50.

Bansal H, Verma P, Agrawal A et al (2016) Autologous bone marrow-derived stem cells in spinal cord injury. J Stem Cells 11:51–61PubMed

51.

Oh SK, Choi KH, Yoo JY et al (2016) A phase III clinical trial showing limited efficacy of autologous mesenchymal stem cell therapy for spinal cord injury. Neurosurgery 78:436–447. https://doi.org/10.1227/NEU.0000000000001056 CrossRefPubMed

52.

Satti HS, Waheed A, Ahmed P et al (2016) Autologous mesenchymal stromal cell transplantation for spinal cord injury: a phase I pilot study. Cytotherapy 18:518–522. https://doi.org/10.1016/j.jcyt.2016.01.004 CrossRefPubMed

53.

Vaquero J, Zurita M, Rico MA et al (2016) An approach to personalized cell therapy in chronic complete paraplegia: the Puerta de Hierro phase I/II clinical trial. Cytotherapy 18:1025–1036. https://doi.org/10.1016/j.jcyt.2016.05.003 CrossRefPubMed

54.

Vaquero J, Zurita M, Rico MA et al (2017) Repeated subarachnoid administrations of autologous mesenchymal stromal cells supported in autologous plasma improve quality of life in patients suffering incomplete spinal cord injury. Cytotherapy 19:349–359. https://doi.org/10.1016/j.jcyt.2016.12.002 CrossRefPubMed

55.

Lammertse D, Tuszynski MH, Steeves JD et al (2007) Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: clinical trial design. Spinal Cord 45:232–242. https://doi.org/10.1038/sj.sc.3102010 CrossRefPubMed

56.

Tuszynski MH, Steeves JD, Fawcett JW et al (2007) Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP Panel: clinical trial inclusion/exclusion criteria and ethics. Spinal Cord 45:222–231. https://doi.org/10.1038/sj.sc.3102009 CrossRefPubMed

57.

Steeves JD, Lammertse D, Curt A et al (2007) Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: clinical trial outcome measures. Spinal Cord 45:206–221. https://doi.org/10.1038/sj.sc.3102008 CrossRefPubMed

58.

Fawcett JW, Curt A, Steeves JD et al (2007) Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneous recovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord 45:190–205. https://doi.org/10.1038/sj.sc.3102007 CrossRefPubMed

59.

Sharma A (2006) Stem cell research in India: emerging scenario and policy concerns. Asian Biotechnol Dev Rev 8:43–53

60.

MacGregor C, Petersen A, Munsie M (2015) Regulation of unproven stem cell therapies—medicinal product or medical procedure? http://www.eurostemcell.org/commentanalysis/regulation-unproven-stem-cell-therapies-medicinal-product-or-medical-procedure

61.

European Medicines Agency/EMA (2010) Concerns over unregulated medicinal products containing stem cells. 16 April EMA/763463

62.

Munsie M, Pera M (2014) Regulatory loophole enables unproven autologous cell therapies to thrive in Australia. Stem Cells Dev 23:34–38. https://doi.org/10.1089/scd.2014.0332 CrossRefPubMed

63.

TGA. Products regulated as biologicals. https://www.tga.gov.au/products-regulated-biologicals. Accessed 1 Jan 2015

64.

Turner L (2015) US stem cell clinics, patient safety, and the FDA. Trends Mol Med 21:271–273. https://doi.org/10.1016/j.molmed.2015.02.008 CrossRefPubMed

65.

Cyranoski D (2012) FDA’s claims over stem cells upheld. Nature 488:14. https://doi.org/10.1038/488014a CrossRefPubMed

66.

National Guidelines on Stem Cell Research (2013) Director general. Indian Council of Medical Research, New Delhi

67.

George B (2011) Regulations and guidelines governing stem cell based products: clinical considerations. Perspect Clin Res 2:94–99. https://doi.org/10.4103/2229-3485.83228 CrossRefPubMedPubMedCentral

68.

Jotwani G, Das SS (2017) National guidelines for stem cell research. Indian Council of Medical Research & Department of Biotechnology, New Delhi

69.

Tiwari SS, Raman S (2014) Governing stem cell therapy in India: regulatory vacuum or jurisdictional ambiguity? New Genet Soc 33:413–433. https://doi.org/10.1080/14636778.2014.970269 CrossRefPubMedPubMedCentral

70.

Jayaraman KS (2005) Indian regulations fail to monitor growing stem-cell use in clinics. Nature 434:259. https://doi.org/10.1038/434259a CrossRefPubMed

71.

Pandya SK (2008) Stem cell transplantation in India: tall claims, questionable ethics. Indian J Med Ethics 5:15–17PubMed

72.

Sipp D (2009) The rocky road to regulation. Nat Rep Stem Cells 23–27. https://doi.org/10.1038/stemcells.2009.125

73.

Cohen CB, Cohen PJ (2010) International stem cell tourism and the need for effective regulation. Part I: stem cell tourism in Russia and India: clinical research, innovative treatment, or unproven hype? Kennedy Inst Ethics J 20:27–49. https://doi.org/10.1353/ken.0.0305 CrossRefPubMed

74.

Salter B, Cooper M, Dickins A, Cardo V (2007) Stem cell science in India: emerging economies and the politics of globalization. Regen Med 2:75–89. https://doi.org/10.2217/17460751.2.1.75 CrossRefPubMed

75.

Bubela T, Li MD, Hafez M et al (2012) Is belief larger than fact: expectations, optimism and reality for translational stem cell research. BMC Med 10:133. https://doi.org/10.1186/1741-7015-10-133 CrossRefPubMedPubMedCentral

76.

Goldring CEP, Duffy PA, Benvenisty N et al (2011) Assessing the safety of stem cell therapeutics. Cell Stem Cell 8:618–628. https://doi.org/10.1016/j.stem.2011.05.012 CrossRefPubMed

77.

Hyun I, Lindvall O, Ahrlund-Richter L et al (2008) New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell 3:607–609. https://doi.org/10.1016/j.stem.2008.11.009 CrossRefPubMed

Titel: Stem cell/cellular interventions in human spinal cord injury: Is it time to move from guidelines to regulations and legislations? Literature review and Spinal Cord Society position statement
verfasst von: Harvinder S. Chhabra
Kanchan Sarda
Geeta Jotwani
M. Gourie-Devi
Erkan Kaptanoglu
Susan Charlifue
S. L. Yadav
B. Mohapatra
Abhishek Srivastava
Kedar Phadke
Publikationsdatum: 16.05.2019
Verlag: Springer Berlin Heidelberg
Erschienen in: European Spine Journal / Ausgabe 8/2019
Print ISSN: 0940-6719
Elektronische ISSN: 1432-0932
DOI: https://doi.org/10.1007/s00586-019-06003-3

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, Videos und Abbildungen.
» Jetzt entdecken

Neu im Fachgebiet Orthopädie und Unfallchirurgie

25.04.2024 | Hypertonie | Nachrichten

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

Stem cell/cellular interventions in human spinal cord injury: Is it time to move from guidelines to regulations and legislations? Literature review and Spinal Cord Society position statement

Abstract

Purpose

Methods

Results

Conclusions

Graphical abstract

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Ärztliche Empathie hilft gegen Rückenschmerzen

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Update Orthopädie und Unfallchirurgie

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

Graphical abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 8/2019

Letter to the Editor concerning “Correlations between sedimentation sign, dural sac cross-sectional area, and clinical symptoms of degenerative lumbar spinal stenosis” by Sangbong Ko (Eur Spine J [2018] 27:1623–1628)

Ligamental compartments and their relation to the passing spinal nerves are detectable with MRI inside the lumbar neural foramina

The use of CT Hounsfield unit values to identify the undiagnosed spinal osteoporosis in patients with lumbar degenerative diseases

Expert’s comment concerning Grand Rounds case entitled “Low energy chronic traumatic spondylolisthesis of the axis” by C. J. Dunn, S. Mease, K. Issa, K. Sinha, A. Emami (Eur Spine J; 2017: DOI 10.1007/s00586-017-5206-4)

Reply to the Letter to the Editor of Jin Yang et al. concerning “Correlations between sedimentation sign, dural sac cross-sectional area, and clinical symptoms of degenerative lumbar spinal stenosis” by Sangbong Ko (Eur Spine J [2018] 27: 1623–1628)

Noise-optimised virtual monoenergetic imaging of dual-energy CT: effect on metal artefact reduction in patients with lumbar internal fixation

Arthropedia

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Therapiestart mit Blutdrucksenkern erhöht Frakturrisiko

Ärztliche Empathie hilft gegen Rückenschmerzen

Stereotaktische Radiatio schlägt konventionelle Bestrahlung

Vorsicht mit hohen NSAR-Dosen bei ankylosierender Spondylitis!

Update Orthopädie und Unfallchirurgie