Cell therapy in Parkinson's disease.
The clinical studies with intrastriatal transplants of fetal mesencephalic tissue in Parkinson's disease (PD) patients have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine (DA) release and movement-related frontal cortical activation, and give rise to significant symptomatic relief. In the most successful cases, patients have been able to withdraw L-dopa treatment after transplantation and resume an independent life. However, there are currently several problems linked to the use of fetal tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients, 2) variability of functional outcome with some patients showing major improvement and others modest if any clinical benefit, and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in PD. For the development of a clinically useful cell therapy, we need to define better criteria for patient selection and how graft placement should be optimized in each patient. We also need to explore in more detail the importance for functional outcome of the dissection and cellular composition of the graft tissue as well as of immunological mechanisms. Strategies to prevent the development of dyskinesias after grafting have to be developed. Finally, we need to generate large numbers of viable DA neurons in preparations that are standardized and quality controlled. The stem cell technology may provide a virtually unlimited source of DA neurons, but several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.
Lindvall
Olle
O
Wallenberg Neuroscience Center and Lund Strategic Center for Stem Cell Biology and Cell Therapy, BMC A11, SE-221 84 Lund, Sweden. olle.lindvall@neurol.lu.se
Björklund
Anders
A
D000818:Animals; D017690:Cell Transplantation; D002986:Clinical Trials as Topic; D004298:Dopamine / Q000502:physiology; D016332:Fetal Tissue Transplantation; D006801:Humans; D010300:Parkinson Disease / Q000628:therapy*; D018579:Patient Selection; D033581:Stem Cell Transplantation
D004298:Dopamine
J Comp Neurol. 1996 Jun 24;370(2):203-30
8808731
Exp Neurol. 2001 May;169(1):23-9
11312554
N Engl J Med. 1992 Nov 26;327(22):1556-63
1435882
Mov Disord. 1998 May;13(3):383-93
9613726
Mov Disord. 2003 Dec;18(12):1442-54
14673880
Exp Neurol. 1996 Nov;142(1):36-46
8912897
Ann Neurol. 1992 Feb;31(2):166-73
1575455
Cell Transplant. 1997 May-Jun;6(3):239-48
9171157
Ann Neurol. 1992 Feb;31(2):155-65
1575454
Eur J Neurosci. 1990;2(4):279-290
12106034
Brain Res. 1995 May 22;680(1-2):180-95
7663976
Ann Neurol. 2003;53 Suppl 3:S135-46; discussion S146-8
12666105
Brain Res. 1988 Apr 1;467(2):233-43
3378172
J Neuropathol Exp Neurol. 2001 Aug;60(8):741-52
11487048
Eur J Neurosci. 1990;2(10):888-894
12106096
Ann Neurol. 1992 Aug;32(2):151-61
1510355
Ann Neurol. 2003 Sep;54(3):403-14
12953276
J Neurosurg. 2002 Mar;96(3):589-96
11883846
Neurology. 2000 Mar 14;54(5):1042-50
10720272
Nat Neurosci. 1999 Dec;2(12):1137-40
10570493
Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2344-9
11782534
Brain Res Dev Brain Res. 1996 Dec 23;97(2):297-303
8997515
Brain Res. 1987 Jul 7;415(1):63-78
3113665
Brain. 1994 Jun;117 ( Pt 3):487-99
8032859
Stereotact Funct Neurosurg. 2002;78(3-4):119-31
12652037
Arch Neurol. 1999 Feb;56(2):179-87
10025423
Brain. 2000 Jul;123 ( Pt 7):1380-90
10869050
Ann Neurol. 1994 Feb;35(2):172-80
8109898
Brain. 1996 Feb;119 ( Pt 1):41-50
8624693
J Neurol. 2000 Apr;247 Suppl 2:II3-10
10991663
Nat Med. 2004 Jul;10 Suppl:S42-50
15272269
N Engl J Med. 1995 Apr 27;332(17):1118-24
7700284
Nature. 2002 Jul 4;418(6893):50-6
12077607
Neuroscience. 1993 Nov;57(2):261-74
7906872
Ann Neurol. 2000 Nov;48(5):689-95
11079531
Exp Neurol. 1996 Oct;141(2):173-80
8812150
Mov Disord. 2003 Aug;18(8):928-32
12889084
J Neurosurg. 2000 May;92(5):863-9
10794303
Neurosci Lett. 1994 Apr 25;171(1-2):32-6
8084493
Acta Physiol Scand Suppl. 1983;522:1-7
6586054
Ann Neurol. 1995 Sep;38(3):379-88
7668823
Biol Rev Camb Philos Soc. 1992 Nov;67(4):491-518
1361154
Prog Brain Res. 2000;127:299-320
11142032
Neuroscience. 1984 May;12(1):17-32
6146944
Ann Neurol. 1995 Oct;38(4):580-8
7574454
Exp Neurol. 2000 Jan;161(1):392-6
10683304
Exp Brain Res. 1995;103(3):355-71
7789442
Science. 1990 Feb 2;247(4942):574-7
2105529
Brain. 1999 Jun;122 ( Pt 6):1121-32
10356064
Brain Res. 2002 Mar 29;931(2):126-34
11897098
Prog Brain Res. 1990;82:141-52
1981274
Nat Neurosci. 2002 Jul;5(7):627-8
12042822
Brain Res. 2000 Feb 21;856(1-2):301-9
10677639
N Engl J Med. 2001 Mar 8;344(10):710-9
11236774
Ann Neurol. 2002 Nov;52(5):628-34
12402261
Brain Res. 2001 Feb 9;891(1-2):228-35
11164827
J Neurosci. 2001 Apr 15;21(8):2889-96
11306640
Ann Neurol. 1997 Jul;42(1):95-107
9225690
Exp Neurol. 1996 Aug;140(2):184-97
8690061
Ann Neurol. 1998 Sep;44(3 Suppl 1):S19-31
9749570
J Cereb Blood Flow Metab. 2003 Jul;23(7):780-5
12843782
Mov Disord. 2002 Mar;17(2):233-41
11921107