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Abstract
Recent advance in the knowledge of stem cell biology and early success in preclinical studies have prompted scientists to design clinical trials for neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). Instead of a cell replacement strategy aiming at unidirectional neuroregeneration, neuroprotective or immune-inflammatory modulations by autologous or allogeneic cell transplantation are becoming central themes in clinical trials. Although stem-cell therapy for intractable neurological disorders is an attractive strategy, numerous essential issues targeting not only safety, efficacy, and source controls, but also clinical protocols, and ethical, regulatory, societal, and cost-benefit effectiveness for stem-cell therapy should be addressed for successful clinical application. Recent promising animal and early clinical data for neurodegenerative disorders might overestimate the hope of stem cell therapy; however, hype is still present for clinical practice. For the successful application of novel stem cell therapy, it is necessary to follow each nation's FDA regulations and international guidelines for the clinical translation of stem cells.
Acknowledgement
This study was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A101712).
References
1. Lindvall O, Kokaia Z. Stem cells in human neurodegenerative disorders: time for clinical translation? J Clin Invest. 2010. 120:29–40.
2. Dantuma E, Merchant S, Sugaya K. Stem cells for the treatment of neurodegenerative diseases. Stem Cell Res Ther. 2010. 1:37.
3. Koh SH, Kim KS, Choi MR, Jung KH, Park KS, Chai YG, Roh W, Hwang SJ, Ko HJ, Huh YM, Kim HT, Kim SH. Implantation of human umbilical cord-derived mesenchymal stem cells as a neuroprotective therapy for ischemic stroke in rats. Brain Res. 2008. 1229:233–248.
4. Keene CD, Ortiz-Gonazalez XR, Jiang Y, Verfaillie CM, Low WC. Sanberg CD, Sanberg PR, editors. Therapeutic application of bone marrow-derived stem cells in neurologic injury and disease. Cell therapy, stem cells, and brain repair. 2006. Totowa (NJ): Humana Press;163–197.
5. Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol. 2000. 164:247–256.
6. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002. 418:41–49.
7. Stem cell research and application skill. Biotech Policy Research Center. 2008. 3:21–23.
8. Research Impact Technologies. Stem cell research: a market insight report. 2008. Andhra Pradesh (India): Research Impact Technologies.
9. Daley GQ, Hyun I, Lindvall O. Mapping the road to the clinical translation of stem cells. Cell Stem Cell. 2008. 2:139–140.
10. Hyun I, Lindvall O, Ahrlund-Richter L, Cattaneo E, Cavazzana-Calvo M, Cossu G, De Luca M, Fox IJ, Gerstle C, Goldstein RA, Hermeren G, High KA, Kim HO, Lee HP, Levy-Lahad E, Li L, Lo B, Marshak DR, McNab A, Munsie M, Nakauchi H, Rao M, Rooke HM, Valles CS, Srivastava A, Sugarman J, Taylor PL, Veiga A, Wong AL, Zoloth L, Daley GQ. New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell. 2008. 3:607–609.
11. Mathews DJ, Sugarman J, Bok H, Blass DM, Coyle JT, Duggan P, Finkel J, Greely HT, Hillis A, Hoke A, Johnson R, Johnston M, Kahn J, Kerr D, Kurtzberg J, Liao SM, McDonald JW, McKhann G, Nelson KB, Rao M, Regenberg A, Siegel AW, Smith K, Solter D, Song H, Vescovi A, Young W, Gearhart JD, Faden R. Cell-based interventions for neurologic conditions: ethical challenges for early human trials. Neurology. 2008. 71:288–293.
12. Boucherie C, Hermans E. Adult stem cell therapies for neuro-logical disorders: benefits beyond neuronal replacement? J Neurosci Res. 2009. 87:1509–1521.
13. Mimeault M, Hauke R, Batra SK. Stem cells: a revolution in therapeutics-recent advances in stem cell biology and their therapeutic applications in regenerative medicine and cancer therapies. Clin Pharmacol Ther. 2007. 82:252–264.
14. Mimeault M, Batra SK. Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies. Stem Cells. 2006. 24:2319–2345.
15. Kim SU, de Vellis J. Stem cell-based cell therapy in neurological diseases: a review. J Neurosci Res. 2009. 87:2183–2200.
16. Ilieva H, Polymenidou M, Cleveland DW. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J Cell Biol. 2009. 187:761–772.
17. Appel SH, Engelhardt JI, Henkel JS, Siklos L, Beers DR, Yen AA, Simpson EP, Luo Y, Carrum G, Heslop HE, Brenner MK, Popat U. Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis. Neurology. 2008. 71:1326–1334.
18. Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavii B, Frackowiak R, Leenders KL, Sawle G, Rothwell JC, Marsden CD, et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science. 1990. 247:574–577.
19. Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, Brin MF, Shannon KM, Nauert GM, Perl DP, Godbold J, Freeman TB. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol. 2003. 54:403–414.
20. Lang AE, Obeso JA. Challenges in Parkinson's disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol. 2004. 3:309–316.
21. Lang AE, Obeso JA. Time to move beyond nigrostriatal dopamine deficiency in Parkinson's disease. Ann Neurol. 2004. 55:761–765.
22. Ince PG, Lowe J, Shaw PJ. Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology. Neuropathol Appl Neurobiol. 1998. 24:104–117.
23. Baek W, Park A, Kim HY, Kim SH. Amyotrophic lateral sclerosis in Korea: clinical characteristics and prognostic factors. J Korean Neurol Assoc. 2011. 29:16–24.
24. Silani V, Cova L, Corbo M, Ciammola A, Polli E. Stem-cell therapy for amyotrophic lateral sclerosis. Lancet. 2004. 364:200–202.
25. Janson CG, Ramesh TM, During MJ, Leone P, Heywood J. Human intrathecal transplantation of peripheral blood stem cells in amyotrophic lateral sclerosis. J Hematother Stem Cell Res. 2001. 10:913–915.
26. Mazzini L, Ferrero I, Luparello V, Rustichelli D, Gunetti M, Mareschi K, Testa L, Stecco A, Tarletti R, Miglioretti M, Fava E, Nasuelli N, Cisari C, Massara M, Vercelli R, Oggioni GD, Carriero A, Cantello R, Monaco F, Fagioli F. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a phase I clinical trial. Exp Neurol. 2010. 223:229–237.
27. Kim HY, Paek JY, Park HK, Choi MR, Yoon HS, Kim KS, Kim SH. Efficacy and safety of autologous bone marrow-derived mesenchymal stem cell treatment in patients with amyotrophic lateral sclerosis. J Korean Neurol Assoc. 2009. 27:163–169.
28. Choi MR, Kim HY, Park JY, Lee TY, Baik CS, Chai YG, Jung KH, Park KS, Roh W, Kim KS, Kim SH. Selection of optimal passage of bone marrow-derived mesenchymal stem cells for stem cell therapy in patients with amyotrophic lateral sclerosis. Neurosci Lett. 2010. 472:94–98.
29. Kim H, Kim HY, Choi MR, Hwang S, Nam KH, Kim HC, Han JS, Kim KS, Yoon HS, Kim SH. Dose-dependent efficacy of ALS-human mesenchymal stem cells transplantation into cisterna magna in SOD1-G93A ALS mice. Neurosci Lett. 2010. 468:190–194.
30. Kim SH, Engelhardt JI, Henkel JS, Siklos L, Soos J, Goodman C, Appel SH. Widespread increased expression of the DNA repair enzyme PARP in brain in ALS. Neurology. 2004. 62:319–322.
31. Cho GW, Noh MY, Kim HY, Koh SH, Kim KS, Kim SH. Bone marrow-derived stromal cells from amyotrophic lateral sclerosis patients have diminished stem cell capacity. Stem Cells Dev. 2010. 19:1035–1042.
32. Price DL, Sisodia SS. Cellular and molecular biology of Alzheimer's disease and animal models. Annu Rev Med. 1994. 45:435–446.
33. Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller FJ, Loring JF, Yamasaki TR, Poon WW, Green KN, LaFerla FM. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A. 2009. 106:13594–13599.
34. Zhongling F, Gang Z, Lei Y. Neural stem cells and Alzheimer's disease: challenges and hope. Am J Alzheimers Dis Other Demen. 2009. 24:52–57.
35. Dezawa M, Kanno H, Hoshino M, Cho H, Matsumoto N, Itokazu Y, Tajima N, Yamada H, Sawada H, Ishikawa H, Mimura T, Kitada M, Suzuki Y, Ide C. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest. 2004. 113:1701–1710.
36. Murrell W, Wetzig A, Donnellan M, Féron F, Burne T, Meedeniya A, Kesby J, Bianco J, Perry C, Silburn P, Mackay-Sim A. Olfactory mucosa is a potential source for autologous stem cell therapy for Parkinson's disease. Stem Cells. 2008. 26:2183–2192.
37. Yasuhara T, Matsukawa N, Hara K, Yu G, Xu L, Maki M, Kim SU, Borlongan CV. Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson's disease. J Neurosci. 2006. 26:12497–12511.
38. Kim JH, Auerbach JM, Rodríguez-Gómez JA, Velasco I, Gavin D, Lumelsky N, Lee SH, Nguyen J, Sanchez-Pernaute R, Bankiewicz K, McKay R. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature. 2002. 418:50–56.
39. Wernig M, Zhao JP, Pruszak J, Hedlund E, Fu D, Soldner F, Broccoli V, Constantine-Paton M, Isacson O, Jaenisch R. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson's disease. Proc Natl Acad Sci U S A. 2008. 105:5856–5861.
40. Shim JW, Park CH, Bae YC, Bae JY, Chung S, Chang MY, Koh HC, Lee HS, Hwang SJ, Lee KH, Lee YS, Choi CY, Lee SH. Generation of functional dopamine neurons from neural precursor cells isolated from the subventricular zone and white matter of the adult rat brain using Nurr1 overexpression. Stem Cells. 2007. 25:1252–1262.
41. Lee HS, Bae EJ, Yi SH, Shim JW, Jo AY, Kang JS, Yoon EH, Rhee YH, Park CH, Koh HC, Kim HJ, Choi HS, Han JW, Lee YS, Kim J, Li JY, Brundin P, Lee SH. Foxa2 and Nurr1 synergistically yield A9 nigral dopamine neurons exhibiting improved differentiation, function, and cell survival. Stem Cells. 2010. 28:501–512.
42. Hwang DY, Kim DS, Kim DW. Human ES and iPS cells as cell sources for the treatment of Parkinson's disease: current state and problems. J Cell Biochem. 2010. 109:292–301.
43. Wenning GK, Colosimo C, Geser F, Poewe W. Multiple system atrophy. Lancet Neurol. 2004. 3:93–103.
44. 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.
45. Lee PH, Park HJ. Bone marrow-derived mesenchymal stem cell therapy as a candidate disease-modifying strategy in Parkinson's disease and multiple system atrophy. J Clin Neurol. 2009. 5:1–10.
46. Park HJ, Bang G, Lee BR, Kim HO, Lee PH. Neuroprotective effect of human mesenchymal stem cells in an animal model of double toxin-induced multiple system atrophy-parkinso-nism. Cell Transplant. 2010. 11. 05. [Epub]. DOI: 10.3727/096368910X540630.
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