BACKGROUND. Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism. METHODS. We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation. RESULTS. Both patients had substantial, sustained improvement in motor function and became much more independent. Postoperatively, the second patient's maintenance dose of levodopa was decreased to 150 mg daily, which was 30 percent of the original dose. Striatal uptake of fluorodopa was unchanged 5 to 6 months postoperatively but was markedly and bilaterally increased at 12 to 13 and 22 to 24 months in both patients, closely paralleling the patients' clinical improvement. There were no serious complications. CONCLUSIONS. Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum. The results in these patients resemble those obtained in MPTP-treated primates and suggest that this will be a useful model for the assessment of transplantation therapies in Parkinson's disease.
Source Information
Department of Neurology, University Hospital, Lund, Sweden.
This article has been cited by other articles:
Carlsson, T., Carta, M., Munoz, A., Mattsson, B., Winkler, C., Kirik, D., Bjorklund, A.
(2009). Impact of grafted serotonin and dopamine neurons on development of L-DOPA-induced dyskinesias in parkinsonian rats is determined by the extent of dopamine neuron degeneration. Brain
132: 319-335
[Abstract][Full Text]
Carlsson, T., Carta, M., Winkler, C., Bjorklund, A., Kirik, D.
(2007). Serotonin Neuron Transplants Exacerbate L-DOPA- Induced Dyskinesias in a Rat Model of Parkinson's Disease. J. Neurosci.
27: 8011-8022
[Abstract][Full Text]
Selkirk, S M
(2004). Gene therapy in clinical medicine. Postgrad. Med. J.
80: 560-570
[Abstract][Full Text]
McRae, C., Cherin, E., Yamazaki, T. G., Diem, G., Vo, A. H., Russell, D., Ellgring, J. H., Fahn, S., Greene, P., Dillon, S., Winfield, H., Bjugstad, K. B., Freed, C. R.
(2004). Effects of Perceived Treatment on Quality of Life and Medical Outcomes in a Double-blind Placebo Surgery Trial. Arch Gen Psychiatry
61: 412-420
[Abstract][Full Text]
Rosser, A E, Barker, R A, Harrower, T, Watts, C, Farrington, M, Ho, A K, Burnstein, R M, Menon, D K, Gillard, J H, Pickard, J, Dunnett, S B
(2002). Unilateral transplantation of human primary fetal tissue in four patients with Huntington's disease: NEST-UK safety report ISRCTN no 36485475. J. Neurol. Neurosurg. Psychiatry
73: 678-685
[Abstract][Full Text]
Redmond, D. E. Jr.
(2002). Book Review: Cellular Replacement Therapy for Parkinson's Disease--Where We Are Today?. Neuroscientist
8: 457-488
[Abstract]
Latchman, D. S.
(2001). Book Review: Gene Therapy with Herpes Simplex Virus Vectors: Progress and Prospects for Clinical Neuroscience. Neuroscientist
7: 528-537
[Abstract]
Mukhida, K., Baker, K. A., Sadi, D., Mendez, I.
(2001). Enhancement of Sensorimotor Behavioral Recovery in Hemiparkinsonian Rats with Intrastriatal, Intranigral, and Intrasubthalamic Nucleus Dopaminergic Transplants. J. Neurosci.
21: 3521-3530
[Abstract][Full Text]
Neff, T., Blau, C. A.
(2001). Pharmacologically regulated cell therapy. Blood
97: 2535-2540
[Full Text]
Freed, C. R., Greene, P. E., Breeze, R. E., Tsai, W.-Y., DuMouchel, W., Kao, R., Dillon, S., Winfield, H., Culver, S., Trojanowski, J. Q., Eidelberg, D., Fahn, S.
(2001). Transplantation of Embryonic Dopamine Neurons for Severe Parkinson's Disease. NEJM
344: 710-719
[Abstract][Full Text]
Brundin, P., Pogarell, O., Hagell, P., Piccini, P., Widner, H., Schrag, A., Kupsch, A., Crabb, L., Odin, P., Gustavii, B., Bjorklund, A., Brooks, D. J., David Marsden, C., Oertel, W. H., Quinn, N. P., Rehncrona, S., Lindvall, O.
(2000). Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease. Brain
123: 1380-1390
[Abstract][Full Text]
SAWLE, G V
(2000). Pattern of dopaminergic loss in the striatum of humans with parkinsonism induced by MPTP. J. Neurol. Neurosurg. Psychiatry
68: 276-276
[Full Text]
Collier, T. J., Sortwell, C. E., Daley, B. F.
(1999). Diminished Viability, Growth, and Behavioral Efficacy of Fetal Dopamine Neuron Grafts in Aging Rats with Long-Term Dopamine Depletion: An Argument for Neurotrophic Supplementation. J. Neurosci.
19: 5563-5573
[Abstract][Full Text]
Hagell, P., Schrag, A., Piccini, P., Jahanshahi, M., Brown, R., Rehncrona, S., Widner, H., Brundin, P., Rothwell, J. C., Odin, P., Wenning, G. K., Morrish, P., Gustavii, B., Bjorklund, A., Brooks, D. J., Marsden, C. D., Quinn, N. P., Lindvall1, O.
(1999). Sequential bilateral transplantation in Parkinson's disease: Effects of the second graft. Brain
122: 1121-1132
[Abstract][Full Text]
Mahoney, M. J., Saltzman, W. M.
(1999). Millimeter-scale positioning of a nerve-growth-factor source and biological activity in the brain. Proc. Natl. Acad. Sci. USA
96: 4536-4539
[Abstract][Full Text]
Mandel, R. J., Rendahl, K. G., Spratt, S. K., Snyder, R. O., Cohen, L. K., Leff, S. E.
(1998). Characterization of Intrastriatal Recombinant Adeno-Associated Virus-Mediated Gene Transfer of Human Tyrosine Hydroxylase and Human GTP-Cyclohydrolase I in a Rat Model of Parkinson's Disease. J. Neurosci.
18: 4271-4284
[Abstract][Full Text]
Freed, C. R., Breeze, R. E., Schneck, S. A., Kordower, J. H., Freeman, T. B., Olanow, C. W.
(1995). Transplantation of Fetal Mesencephalic Tissue in Parkinson's Disease. NEJM
333: 730-731
[Full Text]
Sass, K. J., Buchanan, C. P., Westerveld, M., Marek, K. L., Farhi, A., Robbins, R. J., Naftolin, F., Vollmer, T. L., Leranth, C., Roth, R. H., Price, L. H., Bunney, B. S., Elsworth, J. D., Hoffer, P. B., Redmond, D. E., Spencer, D. D.
(1995). General Cognitive Ability Following Unilateral and Bilateral Fetal Ventral Mesencephalic Tissue Transplantation for Treatment of Parkinson's Disease. Arch Neurol
52: 680-686
[Abstract]
Kordower, J. H., Freeman, T. B., Snow, B. J., Vingerhoets, F. J.G., Mufson, E. J., Sanberg, P. R., Hauser, R. A., Smith, D. A., Nauert, G. M., Perl, D. P., Olanow, C. W.
(1995). Neuropathological Evidence of Graft Survival and Striatal Reinnervation after the Transplantation of Fetal Mesencephalic Tissue in a Patient with Parkinson's Disease. NEJM
332: 1118-1124
[Abstract][Full Text]
Hoffer, B. J., van Horne, C.
(1995). Survival of Dopaminergic Neurons in Fetal-Tissue Grafts. NEJM
332: 1163-1164
[Full Text]
van der Wilt, G. J.
(1995). Alternative Ways of Framing Parkinson's Disease: Implications for Priorities in Health Care and Biomedical Research. Organization Environment
9: 13-48
[Abstract]
During, M. J., Naegele, J. R., O'Malley, K. L., Geller, A. I.
(1994). Long-Term Behavioral Recovery in Parkinsonian Rats by an HSV Vector Expressing Tyrosine Hydroxylase. Science
266: 1399-1403
[Abstract]
Goetz, C. G., Penn, R. D., Klawans, H. L., Van Gilder, J. E., Fung, C. H.K., Lo, J. W., Spencer, D. D., Marek, K. L., Redmond, D. E., Freed, C. R., Breeze, R. E., Rosenberg, N. L., Garry, D. J., Caplan, A. L.
(1993). Fetal-Tissue Transplantation for Parkinson's Disease. NEJM
329: 1498-1500
[Full Text]
Suhr, S. T., Gage, F. H.
(1993). Gene Therapy for Neurologic Disease. Arch Neurol
50: 1252-1268
[Abstract]
Calne, D. B.
(1993). Treatment of Parkinson's Disease. NEJM
329: 1021-1027
[Full Text]
Previous
