Zellersatztherapie beim Morbus Parkinson

Zusammenfassung

Der Ersatz dopaminerger Neurone bei Patienten mit Morbus Parkinson bleibt eine attraktive Behandlungsstrategie. Die Implantation von embryonalem Mittelhirngewebe war die erste Therapie, die nicht nur den »Proof-of-Principle« in Tierversuchen lieferte, sondern auch Eingang in klinische Applikationen fand. 1987 wurde zunächst eine Reihe von kleinen offenen Studien mit sorgfältiger Patientenselektion gestartet, die sehr ermutigende Ergebnisse bei zumindest einem Teil der Patienten erbrachten. In den vergangenen Jahren wurden in den USA zwei doppelblinde, kontrollierte Studien abgeschlossen, deren Resultate eher enttäuschend blieben, da die primären Endpunkte (Besserung der Parkinson-Symptomatik im Off) keine signifikanten Unterschiede zeigten. Zudem wurden in beiden Studien 12 Stunden nach L-Dopa-Einnahme Dyskinesien beobachtet. Die Ursachen dieser unterschiedlichen Ergebnisse könnten in der Variabilität des Gewebes, relevanten Immunreaktionen und ungleichmäßiger Dopaminausschüttung im Striatum liegen. Zudem legen die ethischen Probleme bei der Gewinnung des Gewebes die Notwendigkeit anderer, besser standardisierter Gewebe nahe. Derzeit scheint es möglich, dass alternativ sowohl aus embryonalen als auch neuralen Stammzellen, vielleicht sogar aus körpereigenen mesenchymalen Stammzellen dopaminerge Neurone generiert werden könnten. Diese Zellen können über einen langen Zeitraum expandiert, ausreichend standardisiert und charakterisiert werden.

Summary

Transplantation of dopaminergic neurons remains an attractive treatment option for patients suffering from Parkinson’s disease. The replacement of dopaminergic neurons via implantation of embryonic midbrain tissue was taken from animal experiments to clinical applications. While initial open trials showed positive results at least in some patients, subsequent double blind controlled studies failed to show a significant difference in respect to their primary endpoint (improvement of motor function in the defined off-state). In addition, some patients showed worsening of involuntary movements. Ethical concerns related to the use of fetal tissue derived from abortions further argue for the search for alternative tissue sources. Today it seems possible to generate functional dopaminergic neurons from a variety of stem cells including embryonic and neural stem cells. Bone marrow stromal cells (BMSCs) are another source for cell-replacement. These cells can be converted and then display major characteristics of neural stem cells. Whether these cells could also give rise to autologous functional dopaminergic neurons remains speculative. A major problem, however, is to control cell growth and differentiation of stem cells.

Schlüsselwörter

Morbus Parkinson - Transplantation - Stammzellen - dopaminerge Neurone

Keywords

Parkinson’s disease - transplantation - stem cells - dopaminergic cells

• Literatur

• 1 Bjorklund A. Cell replacement strategies for neurodegenerative disorders. Novartis Found Symp 2000; 231: 7-15.
• 2 Bjorklund LM, Sanchez-Pernaute R, Chung S, Andersson T, Chen IY, McNaught KS, Brownell AL, Jenkins BG, Wahlestedt C, Kim KS, Isacson O. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 2002; 99: 2344-9.
• 3 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: 1701-10.
• 4 Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, Kao R, Dillon S, Winfield H, Culver S, Trojanowski JQ, Eidelberg D, Fahn S. Transplantation of embryonic dopamine neurons for severe Parkinson’s disease. N Engl J Med 2001; 344: 710-9.
• 5 Gage FH. Mammalian neural stem cells. Science 2000; 287: 1433-8.
• 6 Hagell P, Piccini P, Bjorklund A, Brundin P, Rehncrona S, Widner H, Crabb L, Pavese N, Oertel WH, Quinn N, Brooks DJ, Lindvall O. Dyskinesias following neural transplantation in Parkinson’s disease. Nat Neurosci 2002; 5: 627-8.
• 7 Hermann A, Gastl R, Liebau S, Popa MO, Fiedler J, Boehm BO, Maisel M, Lerche H, Schwarz J, Brenner R, Storch A. Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci 2004; 117: 4411-22.
• 8 Hermann A, Gerlach M, Schwarz J, Storch A. Neurorestoration in Parkinson’s disease by cell replacement and endogenous regeneration. Expert Opin Biol Ther 2004; 4: 131-43.
• 9 Isacson O, Bjorklund LM, Schumacher JM. Toward full restoration of synaptic and terminal function of the dopaminergic system in Parkinson’s disease by stem cells. Ann Neurol 2003; 53 (Suppl. 03) S135-46 discussion S146-8.
• 10 Kawasaki H, Suemori H, Mizuseki K, Watanabe K, Urano F, Ichinose H, Haruta M, Takahashi M, Yoshikawa K, Nishikawa S, Nakatsuji N, Sasai Y. Generation of dopaminergic neurons and pigmented epithelia from primate ES cells by stromal cell-derived inducing activity. Proc Natl Acad Sci USA 2002; 99: 1580-5.
• 11 Kim JH, Auerbach JM, Rodriguez-Gomez 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: 50-6.
• 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: 675-9.
• 13 Lindvall O, Backlund EO, Farde L, Sedvall G, Freedman R, Hoffer B, Nobin A, Seiger A, Olson L. Transplantation in Parkinson’s disease: two cases of adrenal medullary grafts to the putamen. Ann Neurol 1987; 22: 457-68.
• 14 Lindvall O, Hagell P. Cell therapy and transplantation in Parkinson’s disease. Clin Chem Lab Med 2001; 39: 356-61.
• 15 Lindvall O, Sawle G, Widner H, Rothwell JC, Bjorklund A, Brooks D, Brundin P, Frackowiak R, Marsden CD, Odin P. et al. Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson’s disease. Ann Neurol 1994; 35: 172-80.
• 16 Ma Y, Feigin A, Dhawan V, Fukuda M, Shi Q, Greene P, Breeze R, Fahn S, Freed C, Eidelberg D. Dyskinesia after fetal cell transplantation for parkinsonism: a PET study. Ann Neurol 2002; 52: 628-34.
• 17 Madrazo I, Drucker-Colin R, Diaz V, Martinez-Mata J, Torres C, Becerril JJ. Open microsurgical autograft of adrenal medulla to the right caudate nucleus in two patients with intractable Parkinson’s disease. N Engl J Med 1987; 316: 831-4.
• 18 Marshall E. The business of stem cells. Science 2000; 287: 1419-21.
• 19 Milosevic J, Schwarz SC, Krohn K, Poppe M, Storch A, Schwarz J. Low atmospheric oxygen avoids maturation, sensecence and cell death of murine mesencephalic neural precursors. J Neurochem. (in press).
• 20 Milosevic J, Storch A, Schwarz J. Spontaneous apoptosis in murine free-floating neurospheres. Exp Cell Res 2004; 294: 9-17.
• 21 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: 403-14.
• 22 Park S, Lee KS, Lee YJ, Shin HA, Cho HY, Wang KC, Kim YS, Lee HT, Chung KS, Kim EY, Lim J. Generation of dopaminergic neurons in vitro from human embryonic stem cells treated with neurotrophic factors. Neurosci Lett 2004; 359: 99-103.
• 23 Piccini P, Brooks DJ, Bjorklund A, Gunn RN, Grasby PM, Rimoldi O, Brundin P, Hagell P, Rehncrona S, Widner H, Lindvall O. Dopamine release from nigral transplants visualized in vivo in a Parkinson’s patient. Nat Neurosci 1999; 2: 1137-40.
• 24 Redmond Jr DE, Roth RH, Spencer DD, Naftolin F, Leranth C, Robbins RJ, Marek KL, Elsworth JD, Taylor JR, Sass KJ. Neural transplantation for neurodegenerative diseases: past, present, and future. Ann NY Acad Sci 1993; 695: 258-66.
• 25 Riaz SS, Jauniaux E, Stern GM, Bradford HF. The controlled conversion of human neural progenitor cells derived from foetal ventral mesencephalon into dopaminergic neurons in vitro. Brain Res Dev Brain Res 2002; 136: 27-34.
• 26 Sanchez-Pernaute R, Studer L, Bankiewicz KS, Major EO, McKay RD. In vitro generation and transplantation of precursor-derived human dopamine neurons. J Neurosci Res 2001; 65: 284-8.
• 27 Storch A, Lester HA, Boehm BO, Schwarz J. Functional characterization of dopaminergic neurons derived from rodent mesencephalic progenitor cells. J Chem Neuroanat 2003; 26: 133-42.
• 28 Storch A, Paul G, Csete M, Boehm BO, Carvey PM, Kupsch A, Schwarz J. Long-term proliferation and dopaminergic differentiation of human mesencephalic neural precursor cells. Exp Neurol 2001; 170: 317-25.
• 29 Studer L, Tabar V, McKay RD. Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci 1998; 1: 290-5.
• 30 Titan Pharmaceuticals, Inc. Spheramine^® http://www.titanpharm.com/products/spheramine_product.html
• 31 Wang X, Lu Y, Zhang H, Wang K, He Q, Wang Y, Liu X, Li L. Distinct efficacy of pre-differentiated versus intact fetal mesencephalon-derived human neural progenitor cells in alleviating rat model of Parkinson’s disease. Int J Dev Neurosci 2004; 22: 175-83.