Experimentelle Therapiestrategien

A. Storch; M. Löhle

doi:10.1055/s-0038-1628774

Nervenheilkunde, Table of Contents

Nervenheilkunde 2010; 29(06): 372-377
DOI: 10.1055/s-0038-1628774

Parkinson

Schattauer GmbH

Experimentelle Therapiestrategien

Ansätze für eine neurorestaurative Behandlung des Morbus ParkinsonExperimental therapy strategiesApproaches for neurorestaurative treatment of Parkinson’s disease

A. Storch

¹Klinik und Poliklinik für Neurologie, Technische Universität Dresden

²Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden

,

M. Löhle

¹Klinik und Poliklinik für Neurologie, Technische Universität Dresden

› Author Affiliations

Abstract

Zusammenfassung

Für die restaurative Therapie verloren gegangener Zell- und Gewebefunktionen hat sich der Einsatz von Stammzellen in vielen medizinischen Bereichen als attraktive Strategie erwiesen, sodass Stammzelltherapien in einigen Fachgebieten mittlerweile zum klinischen Alltag gehören. Die Komplexität des Gewebes im zentralen Nervensystem beschränkt die therapeutischen Anstrengungen häufig auf die Rekonstitution umschriebener, gut bekannter Neurotransmitterdefizite, wie beispielsweise die Rekonstitution des nigrostriatalen Systems beim Morbus Parkinson. So wurden in den letzten Jahren eine Vielzahl neuer innovativer Stammzellquellen für die Zellersatztherapie des Morbus Parkinson entwickelt. Dazu zählen die embryonalen Stammzellen, adulte und fetale gewebsspezifische neurale Stammzellen und die neuen induzierten pluripotenten Stammzellen, die für autologe Therapiestrategien verfügbar wären. Daneben wurden durch die Entwicklung von innovativen Biomaterialien neue orthotope Strategien möglich, die möglicherweise eine Rekonstruktion des dopaminergen nigrostriatalen Systems erlauben. In dieser Arbeit möchten wir verschiedene Strategien der Nutzung von Stammzellen zur Therapie des Morbus Parkinson vorstellen und deren mögliche klinische Anwendung kritisch diskutieren.

Summary

Stem cell therapy represents an attractive approach for the restoration of compromised cell and tissue function in various diseases and has already become an integrative part of clinical treatment in some fields of medicine. The complexity of the central nervous system limits therapeutic interventions in neurological diseases to the reconstitution of selective and circumscribed neurotransmitter deficits, such as the restoration of the nigrostriatal system in Parkinson’s disease. During recent years, various new stem cell sources have been examined for cell replacement therapies in Parkinson’s disease, such as embryonic stem cells, adult and fetal neural stem cells as well as the newly discovered induced pluripotent stem cells, which could be used for autologous transplantations. Moreover, orthotopic cell replacement has become a possible treatment option due to the development of modern biomaterials, which may facilitate the reconstruction of the dopaminergic nigrostriatal pathway in future. In this paper we present possible strategies for the therapeutic use of stem cells in Parkinson’s disease and critically discuss their clinical application.

Schlüsselwörter

Stammzelltherapie - Morbus Parkinson - induzierte pluripotente Stammzellen - Neurorestauration - Neurotransplantation

Keywords

Stem cell therapy - Parkinson’s disease - induced pluripotent stem cells - neurorestoration - neurotransplantation

Full Text

References

Literatur
1 Dorsey ER. et al. Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030. Neurology 2007; 68: 384-6.
2 Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967; 15: 427-42.
3 Martilla PJ, Rinne UK. Disability and progression in Parkinson’s disease. Acta Neurol Scand 1977; 56: 159-69.
4 Poewe W. The natural history of Parkinson’s disease. J Neurol 2006; 253 (Suppl. 07) VII2-6.
5 Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’s disease. A community-based study 2000; 123 (Pt 11): 2297-305.
6 Weaver FM. et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. Jama 2009; 301 (01) 63-73.
7 Deuschl G. et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med 2006; 355 (09) 896-908.
8 Witt K. et al. Neuropsychological and psychiatric changes after deep brain stimulation for Parkinson’s disease: a randomised, multicentre study. Lancet Neurol 2008; 07 (07) 605-14.
9 Amit M. et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol 2000; 227 (02) 271-8.
10 Kawasaki H. et al. Induction of midbrain dopaminergic neurons from ES cells by stromal cell-derived inducing activity. Neuron 2000; 28 (01) 31-40.
11 Bradley A, Evans M, Kaufman MH, Robertson E. Formation of germ-line chimaeras from embryoderived teratocarcinoma cell lines. Nature 1984; 309 5965 255-6.
12 Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 2000; 18 (06) 675-9.
13 Cho MS, Hwang DY, Kim DW. Efficient derivation of functional dopaminergic neurons from human embryonic stem cells on a large scale. Nat Protoc 2008; 03 (12) 1888-94.
14 Cho MS. et al. Highly efficient and large-scale generation of functional dopamine neurons from human embryonic stem cells. Proc Natl Acad Sci USA 2008; 105 (09) 3392-7.
15 Kim JH. et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson’s disease. Nature 2002; 418 (6893): 50-6.
16 Bjorklund LM. et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 2002; 99 (04) 2344-9.
17 Takagi Y. et al. Dopaminergic neurons generated from monkey embryonic stem cells function in a Parkinson primate model. J Clin Invest 2005; 115 (01) 102-9.
18 Inden M. et al. Transplantation of mouse embryonic stem cell-derived neurons into the striatum, subthalamic nucleus and substantia nigra, and behavioral recovery in hemiparkinsonian rats. Neurosci Lett 2005; 387 (03) 151-6.
19 Zeng X. et al. Dopaminergic differentiation of human embryonic stem cells. Stem Cells 2004; 22 (06) 925-40.
20 Park CH. et al. In vitro and in vivo analyses of human embryonic stem cell-derived dopamine neurons. J Neurochem 2005; 92 (05) 1265-76.
21 Erdo F. et al. Host-dependent tumorigenesis of embryonic stem cell transplantation in experimental stroke. J Cereb Blood Flow Metab 2003; 23 (07) 780-5.
22 Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126 (04) 663-76.
23 Takahashi K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007; 131 (05) 861-72.
24 Wernig M. et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci USA 2008; 105 (15) 5856-61.
25 Stadtfeld M, Nagaya M, Utikal J, Weir G, Hochedlinger K. Induced pluripotent stem cells generated without viral integration. Science 2008; 322 (5903): 945-9.
26 Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S. Generation of mouse induced pluripotent stem cells without viral vectors. Science 2008; 322 (5903): 949-53.
27 Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K. Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 2009; 458 (7239): 771-5.
28 Woltjen K. et al. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 2009; 458 (7239): 766-70.
29 Soldner F. et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell 2009; 136 (05) 964-77.
30 Kim JB. et al. Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors. Nature 2008; 454 (7204): 646-50.
31 Kim JB. et al. Oct4-induced pluripotency in adult neural stem cells. Cell 2009; 136 (03) 411-9.
32 Zhou H. et al. Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 2009; 04 (05) 381-4.
33 Kim D. et al. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 2009; 04 (06) 472-6.
34 Freed CR. et al. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001; 44 (10) 710-9.
35 Olanow CW. et al. A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003; 54 (03) 403-14.
36 Nikkhah G, Cunningham MG, Cenci MA, McKay RD, Bjorklund A. Dopaminergic microtransplants into the substantia nigra of neonatal rats with bilateral 6-OHDA lesions. I. Evidence for anatomical reconstruction of the nigrostriatal pathway. J Neurosci 1995; 15 (5 Pt 1): 3548-61.
37 Mendez I, Sadi D, Hong M. Reconstruction of the nigrostriatal pathway by simultaneous intrastriatal and intranigral dopaminergic transplants. J Neurosci 1996; 16 (22) 7216-27.
38 Zhou FC, Chiang YH, Wang Y. Constructing a new nigrostriatal pathway in the Parkinsonian model with bridged neural transplantation in substantia nigra. J Neurosci 1996; 16 (21) 6965-74.
39 Bentlage C, Nikkhah G, Cunningham MG, Bjorklund A. Reformation of the nigrostriatal pathway by fetal dopaminergic micrografts into the substantia nigra is critically dependent on the age of the host. Exp Neurol 1999; 159 (01) 177-90.
40 Baker KA, Mendez I. Long distance selective fiber outgrowth of transplanted hNT neurons in white matter tracts of the adult rat brain. J Comp Neurol 2005; 486 (04) 318-30.
41 Mendez I. et al. Simultaneous intrastriatal and intranigral fetal dopaminergic grafts in patients with Parkinson disease: a pilot study. Report of three cases. J Neurosurg 2002; 96 (03) 589-96.
42 Mendez I. et al. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain 2005; 128 (Pt 7): 1498-510.
43 Gaillard A. et al. Anatomical and functional reconstruction of the nigrostriatal pathway by intranigral transplants. Neurobiol Dis 2009; 35 (03) 477-88.
44 Thompson LH, Grealish S, Kirik D, Bjorklund A. Reconstruction of the nigrostriatal dopamine pathway in the adult mouse brain. Eur J Neurosci 2009; 30 (04) 625-38.
45 Wilby MJ. et al. A glial cell line-derived neurotrophic factor-secreting clone of the Schwann cell line SCTM41 enhances survival and fiber outgrowth from embryonic nigral neurons grafted to the striatum and to the lesioned substantia nigra. J Neurosci 1999; 19 (06) 2301-12.
46 Chiang Y, Morales M, Zhou FC, Borlongan C, Hoffer BJ, Wang Y. Fetal intra-nigral ventral mesencephalon and kidney tissue bridge transplantation restores the nigrostriatal dopamine pathway in hemiparkinsonian rats. Brain Res 2001; 889 (1–2): 200-7.
47 Subramanian A, Krishnan UM, Sethuraman S. Development of biomaterial scaffold for nerve tissue engineering: Biomaterial mediated neural regeneration. J Biomed Sci 2009; 16: 108.
48 Discher DE, Janmey P, Wang YL. Tissue cells feel and respond to the stiffness of their substrate. Science 2005; 310 5751 1139-43.
49 Yeung T. et al. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil Cytoskeleton 2005; 60 (01) 24-34.
50 Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell 2006; 126 (04) 677-89.
51 Freudenberg U. et al. A star-PEG-heparin hydrogel platform to aid cell replacement therapies for neurodegenerative diseases. Biomaterials 2009; 30 (28) 5049-60.
52 Gage FH. Mammalian neural stem cells. Science 2000; 287 (5457): 1433-8.
53 Goh EL, Ma D, Ming GL, Song H. Adult neural stem cells and repair of the adult central nervous system. J Hematother Stem Cell Res 2003; 12 (06) 671-9.
54 Alvarez-Buylla A, Lim DA. For the long run: maintaining germinal niches in the adult brain. Neuron 2004; 41 (05) 683-6.
55 Ma DK, Ming GL, Song H. Glial influences on neural stem cell development: cellular niches for adult neurogenesis. Curr Opin Neurobiol 2005; 15 (05) 514-20.
56 Ming GL, Song H. Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 2005; 28: 223-50.
57 Duan X, Kang E, Liu CY, Ming GL, Song H. Development of neural stem cell in the adult brain. Curr Opin Neurobiol 2008; 18 (01) 108-15.
58 Zhao C, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell 2008; 132 (04) 645-60.
59 Magavi SS, Leavitt BR, Macklis JD. Induction of neurogenesis in the neocortex of adult mice. Nature 2000; 405 (6789): 951-5.
60 Jiang W, Gu W, Brannstrom T, Rosqvist R, Wester P. Cortical neurogenesis in adult rats after transient middle cerebral artery occlusion. Stroke 2001; 32 (05) 1201-7.
61 Jin K. et al. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci 2003; 24 (01) 171-89.
62 Zhao M. et al. Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci USA 2003; 100 (13) 7925-30.
63 Shan X. et al. Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineinduced Parkinson’s disease-like mice. Stem Cells 2006; 24 (05) 1280-7.
64 Frielingsdorf H, Schwarz K, Brundin P, Mohapel P. No evidence for new dopaminergic neurons in the adult mammalian substantia nigra. Proc Natl Acad Sci USA 2004; 101 (27) 10177-82.
65 Tande D, Hoglinger G, Debeir T, Freundlieb N, Hirsch EC, Francois C. New striatal dopamine neurons in MPTP-treated macaques result from a phenotypic shift and not neurogenesis. Brain 2006; 129 (Pt 5): 1194-200.
66 Hermann A, Storch A. Endogenous regeneration in Parkinson’s disease: do we need orthotopic dopaminergic neurogenesis?. Stem Cells 2008; 26 (11) 2749-52.
67 Hermann A. et al. Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons. Stem Cells 2006; 24 (04) 949-64.
68 Hermann A. et al. Rostro-caudal gradual loss of cellular diversity within the periventricular regions of the ventricular system. Stem Cells 2009; 27 (04) 928-41.
69 Lie DC, Dziewczapolski G, Willhoite AR, Kaspar BK, Shults CW, Gage FH. The adult substantia nigra contains progenitor cells with neurogenic potential. J Neurosci 2002; 22 (15) 6639-49.