Stem Cell Therapy for Amyotrophic Lateral Sclerosis – an Overview of Current Clinical Experience
Authors:
D. Baumgartner; P. Marusič; R. Mazanec
Authors‘ workplace:
Neurologická klinika 2. LF UK a FN Motol, Praha
Published in:
Cesk Slov Neurol N 2017; 80/113(1): 27-33
Category:
Review Article
doi:
https://doi.org/10.14735/amcsnn201727
Overview
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of motor neurons. While the genetics behind familial as well as sporadic ALS are being increasingly uncovered, pathophysiology remains incompletely understood and there are no effective treatment options. However, as preclinical results provided some rationale for the use of stem cells as support cells for the dying motor neurons, stem cells are being considered as a potential treatment strategy. Based on the preclinical models, translational human trials have been carried out using various types of stem cells, as well as a range of cell delivery methods. To date, no trial has demonstrated a clear therapeutic benefit. Here, we provide a critical review of current clinical trials using either mesenchymal or neural stem cells to treat ALS patients. In order to provide robust assessment of the efficacy of stem cells, it will be essential to standardize administration protocols, identify the most suitable cell type as well as to validate more reliable biomarkers of disease progression in longitudinal clinical studies.
Key words:
amyotrophic lateral sclerosis – stem cell therapy – neural progenitor cells – mesenchymal stem cells – granulocyte-colony stimulating factor – clinical trials
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.
Sources
1. Chiò A, Logroscino G,Traynor BJ, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 2013;41(2):118– 30. doi: 10.1159/ 000351153.
2. Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 2013; 14(4):248– 64. doi: 10.1038/ nrn3430.
3. Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 2014;17(1):17– 23. doi: 10.1038/ nn.3584.
4. Chen-Plotkin AS, Lee VM, Trojanowski JQ. TAR DNA--binding protein 43 in neurodegenerative disease. Nat Rev Neurol 2010;6(4):211– 20. doi: 10.1038/ nrneurol.2010.18.
5. Turner MR, Hardiman O, Benatar M, et al. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol 2013;12(3):310– 22. doi: 10.1016/ S1474-4422(13)70036-X.
6. Mitsumoto H, Brook BR, Silani V. Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol 2014;13(11):1127– 38. doi: 10.1016/ S1474-4422(14)70129-2.
7. Gordon P, Corcia P, Meininger V. New therapy options for amyotrophic lateral sclerosis. Expert Opin Pharmacother 2013;14(14):1907– 17. doi: 10.1517/ 14656566.2013.819344.
8. Hwang DH, Lee HJ, Park IH, et al. Intrathecal transplantation of human neural stem cells overexpressing VEGF provide behavioral improvement, disease onset delay and survival extension in transgenic ALS mice. Gene Ther 2009;16(10):1234– 44. doi: 10.1038/ gt.2009.80.
9. Vercelli A, Mereuta OM, Garbossa D, et al. Human mesenchymal stem cell transplantation extends survival, improves motor performance and decreases neuroinflammation in mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 2008;31(3):395– 405. doi: 10.1016/ j.nbd.2008.05.016.
10. Lepore AC, Rauck B, Dejea C, et al. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nature Neurosci 2008;11(11):1294– 301. doi: 10.1038/ nn.2210.
11. Teng YD, Benn SC, Kalkanis SN, et al. Multimodal actions of neural stem cells in a mouse model of ALS: a meta-analysis. Sci Transl Med 2012;4(165):165ra164. doi: 10.1126/ scitranslmed.3004579.
12. Goutman SA, Chen KS, Feldman EL. Recent advances and the future of stem cell therapies in amyotrophic lateral sclerosis. Neurotherapeutics 2015;12(2):428– 48. doi: 10.1007/ s13311-015-0339-9.
13. OCEBM Levels of Evidence Working Group. The Oxford 2011 Levels of Evidence. Oxford Centre for Evidence-Based Medicine. [online]. Available from URL: http://www.cebm.net/index.aspx?o=5653.
14. Nefussy B, Artamonov I, Deutsch V, et al. Recombinant human granulocyte-colony stimulating factor administration for treating amyotrophic lateral sclerosis: a pilot study. Amyotroph Lateral Scler 2010;11(1– 2):187– 93. doi: 10.3109/17482960902933809.
15. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010;67(10):1187– 94. doi: 10.1001/ archneurol.2010.248.
16. Gordon PH, Cheng B, Salachas F, et al. Progression in ALS is not linear but is curvilinear. J Neurol 2010;257(10):1713– 7. doi: 10.1007/ s00415-010-5609-1.
17. Mandrioli J, Biguzzi S, Guidi C, et al. Heterogeneity in ALSFRS-R decline and survival: a population based study in Italy. Neurol Sci 2015;36(12):2243– 52. doi: 10.1007/s10072-015-2343-6.
18. Kim HY, Kim H, Oh KW, et al. Biological markers of mesenchymal stromal cells as predictors of response to autologous stem celltransplantation in patients with amyotrophic lateral sclerosis: an investigator-initiated trial and in vivo study. Stem Cells 2014;32(10):2724– 31. doi: 10.1002 / stem.1770.
19. Oh KW, Moon C, Kim HY, et al. Phase I trial of repeated intrathecal autologous bone marrow-derived mesenchymal stromal cells in amyotrophiclateral sclerosis. Stem Cells Transl Med 2015;4(6):590– 7. doi: 10.5966/sctm.2014-0212.
20. Petrou P, Gothelf Y, Argov Z, et al. Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation inp with amyotrophic lateral sclerosis: results of phase 1/ 2 and 2a clinical trials. JAMA Neurol 2016;73(3):337– 44. doi: 10.1001/ jamaneurol.2015.4321.
21. Castrillo-Viguera C, Grasso DL, Simpson E. Clinical significance in the change of decline in ALSFRS-R. Amyotroph Lateral Scler 2010;11(1– 2):178– 80. doi: 10.3109/ 17482960903093710.
22. Gomeni R, Fava M, PRO-ACT Database. Amyotrophic lateral sclerosis disease progression model. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:119– 29. doi: 10.3109/ 21678421.2013.838970.
23. Bedlack RS, Vaughan T, Wicks P, et al. How common are ALS plateaus and reversals? Neurology 2016;86(9):808– 12. doi: 10.1212/ WNL.0000000000002251.
24. Simon NG, Turner MR, Vucic S, et al. Quantifying disease progression in amyotrophic lateral sclerosis. Ann Neurol 2014;76(5):643– 57. doi: 10.1002/ ana.24273.
25. Mazzini L, Mareschi K, Ferrero I, et al. Mesenchymal stromal cell transplantation in amyotrophic lateral sclerosis: a long-term safety study. Cytotherapy 2012;14(1):56– 60. doi: 10.3109/ 14653249.2011.613929.
26. Matuz T, Birbaumer N, Hautzinger M, et al. Coping with amyotrophic lateral sclerosis: an integrative view. J Neurol Neurosurg Psychiatry 2010;81(8):893– 8. doi: 10.1136/ jnnp.2009.201285.
27. Blanquer M, Moraleda JM, Iniesta F, et al. Neurotrophic bone marrow cellular nests prevent spinal motoneuron degeneration in amyotrophic lateral sclerosis patients: a pilot safety study. Stem Cells 2012;30(6):1277– 85. doi: 10.1002/ stem.1080.
28. Deda H, Inci MC, Kürekçi AE, et al. Treatment of amyotrophic lateral sclerosis patients, by autologous bone marrow-derived hematopoietic stem cell transplantation: a 1-year follow-up. Cytotherapy 2009;11(1):18– 25. doi: 10.1080/ 14653240802549470.
29. Feldman EL, Boulis NM, Hur J, et al. Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol 2014;75(3):363– 73. doi: 10.1002/ ana.24113.
30. Mazzini L, Gelati M, Profico DC, et al. Human neural stem cell transplantation in ALS: initial results from a phase I trial. J Transl Med 2015;13:17. doi: 10.1186/ s12967-014-0371-2.
31. Martinez HR, Gonzalez-Garza MT, Moreno-Cuevas JE, et al. Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients. Cytotherapy 2009;11(1):26– 34. doi: 10.1080/ 14653240802644651.
32. Benatar M. Lost in translation: treatment trials in the SOD1 mouse and in human ALS. Neurobiol Dis 2007;26(1):1– 13. doi: 10.1016/ j.nbd.2006.12.015.
33. Chiò A, Calvo A, Moglia C, et al. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study. J Neurol Neurosurg Psychiatry 2011;82(7):740– 6. doi: 10.1136/ jnnp.2010.235952.
34. van der Worp HB, Howells DW, Sena ES, et al. Can animal models of disease reliably inform human studies? PLoS Med 2010;7(3):e1000245. doi: 10.1371/ journal.pmed.1000245.
35. Ludolph AC, Bendotti C, Blaugrund E, et al. Guidelines for preclinical animal research in ALS/ MND: a consensus meeting. Amyotroph Lateral Scler 2010;11(1– 2):38– 45. doi: 10.3109/ 17482960903545334.
36. Coatti GC, Beccari MS, Olávio TR, et al. Stem cellsfor amyotrophic lateral sclerosis modeling and therapy: myth or fact? Cytometry A 2015;87(3):197– 211. doi: 10.1002/ cyto.a.22630.
37. Scruggs BA, Semon JA, Zhang X, et al. Age of the donor reduces the ability of human adipose-derived stem cells to alleviate symptoms in the experimental autoimmune encephalomyelitis mouse model. Stem Cells Transl Med 2013;2(10):797– 807. doi: 10.5966/ sctm.2013-0026.
38. Koh SH, Baik W, Noh MY, et al. The functional deficiency of bone marrow mesenchymal stromal cells in ALS patients is proportional to disease progression rate. Exp Neurol 2012;233(1):472– 80. doi: 10.1016/ j.expneurol.2011.11.021.
39. Boucherie C, Caumont AS, Maloteaux JM, et al. In vitro evidence for impaired neuroprotective capacities of adult mesenchymal stem cells derived from a rat model of familial amyotrophic lateral sclerosis (hSOD1(G93A)). Exp Neurol 2008;212(2):557– 61. doi: 10.1016/ j.expneurol.2008.04.030.
40. Hefferan MP, Johe K, Hazel T, et al. Optimization of immunosuppressive therapy for spinal grafting of human spinal stem cells in a rat model of ALS. Cell Transplant 2011;20(8):1153– 61. doi: 10.3727/ 096368910X564553.
41. Hefferan MP, Galik J, Kakinohana O, et al. Human neural stem cell replacement therapy for amyotrophic lateral sclerosis by spinal transplantation. PLoS One 2012;7(8):e42614. doi: 10.1371/ journal.pone.0042614.
42. Zhang C, Zhou C, Teng JJ, et al. Multiple administrations of human marrow stromal cells through cerebrospinal fluid prolong survival in a transgenic mouse model of amyotrophic lateral sclerosis. Cytotherapy 2009;11(3):299– 306. doi: 10.1080 / 14653240902806986.
43. Kim H, Kim HY, Choi MR, et al. Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice.Neurosci Lett 2010;468(3):190– 4. doi: 10.1016/ j.neulet.2009.10.074.
44. Pinto S, Swash M, de Carvalho M. Does surgery accelerate progression of amyotrophic lateral sclerosis? J Neurol Neurosurg Psychiatry 2014;85(6):643– 6. doi: 10.1136/ jnnp-2013-305770.
45. Lalu MM, McIntyre L, Pugliese C, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One 2012;7(10):e47559. doi: 10.1371/ journal.pone.0047559.
46. Amariglio N, Hirshberg A, Scheithauer BW, et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med 2009;6(2):e1000029. doi: 10.1371/ journal.pmed.1000029.
47. Franchignoni F, Mora G, Giordano A, et al. Evidence of multidimensionality in the ALSFRS-R Scale: a critical appraisal on its measurement properties using Rasch analysis. J Neurol Neurosurg Psychiatry 2013;84(12):1340– 5. doi: 10.1136/ jnnp-2012-304701.
48. Proudfoot M, Jones A, Talbot K, et al. The ALSFRS as an outcome measure in therapeutic trials and its relationship to symptom onset. Amyotroph Lateral Scler Frontotemporal Degener 2016;17(5– 6):414– 25. doi: 10.3109/ 21678421.2016.1140786.
49. Elamin M, Bede P, Montuschi A, et al. Predicting prognosis in amyotrophic lateral sclerosis: a simple algorithm. J Neurol 2015;262(6):1447– 54. doi: 10.1007/ s00415-015-7731-6.
50. Sharma A, Khan JS, Devereaux PJ. Is crowdfunding a viable source of clinical trial research funding? Lancet 2015; 386(9991):338. doi: 10.1016/ S0140-6736(15)61407-6.
Labels
Paediatric neurology Neurosurgery NeurologyArticle was published in
Czech and Slovak Neurology and Neurosurgery
2017 Issue 1
Most read in this issue
- Essential Neurological Examination – Time for Change?
- Current Perception of Contraindications and Complications of Nerve Conduction Studies and Needle Electromyography
- Extirpation of Colloid Cyst by an Endoscopic Approach
- Periodic Limb Movements During Sleep are More Severe in Narcolepsy with Cataplexy than in Narcolepsy without Cataplexy