A double‐blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease

Abstract

Thirty-four patients with advanced Parkinson's disease participated in a prospective 24-month double-blind, placebo-controlled trial of fetal nigral transplantation. Patients were randomized to receive bilateral transplantation with one or four donors per side or a placebo procedure. The primary end point was change between baseline and final visits in motor component of the Unified Parkinson's Disease Rating Scale in the practically defined off state. There was no significant overall treatment effect (p = 0.244). Patients in the placebo and one-donor groups deteriorated by 9.4 +/- 4.25 and 3.5 +/- 4.23 points, respectively, whereas those in the four-donor group improved by 0.72 +/- 4.05 points. Pairwise comparisons were not significant, although the four-donor versus placebo groups yielded a p value of 0.096. Stratification based on disease severity showed a treatment effect in milder patients (p = 0.006). Striatal fluorodopa uptake was significantly increased after transplantation in both groups and robust survival of dopamine neurons was observed at postmortem examination. Fifty-six percent of transplanted patients developed dyskinesia that persisted after overnight withdrawal of dopaminergic medication ("off"-medication dyskinesia). Fetal nigral transplantation currently cannot be recommended as a therapy for PD based on these results.

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

“…Thus, these data suggest that supplementing intrastriatal fetal VM grafts with in vivo injections of viral vector delivering the GDNF gene may decrease the number of VM grafts necessary to re-supply the host striatum with adequate levels of DA. This would be a significant achievement, as the use of eight donors for one human host (Hauser et al, 1999;Olanow et al, 2003) is an obstacle to neural grafting as a treatment option for Parkinson's disease.…”

“…Some parkinsonian patients that received fetal VM grafts in recent clinical trials developed off-medication dyskinesias or graft-induced dyskinesias (GID) (Freed et al, 2001;Hagell et al, 2002;Olanow et al, 2003). The proportion of patients in these 3 studies with GID severe enough to constitute clinical therapeutic problems has been estimated to be between 7 and 15% (Hagell and Cenci, 2005).…”

“…Animal studies in the rodent (reviewed by Brundin et al, 1994), and in the primate (Annett, 1994;Bankiewicz et al, 1993;Elsworth et al, 1996;Fine et al, 1988;Taylor et al, 1991) have shown that grafts of fetal DA neurons can lead to reversals in biochemical and behavioral indices of DA deficiency. However, in clinical studies the improvements in Parkinsonism have been variable, and generally rather modest (Freed et al, 1992;Freed et al, 2001;Lindvall and Hagell, 2001;Olanow et al, 2003;Redmond, 2002;Spencer et al, 1992;Widner et al, 1992).…”

Cell Therapeutics in Parkinson's Disease

“…Dopaminergic Grafts Can Survive and Become Morphologically Integrated in the PD Patient's Brain Following implantation of postmitotic DA neuroblasts from the ventral mesencephalon of 6-to 9-weekold human fetuses, positron emission tomography (PET) detected increases in 6-L-[ 18 F]-fluorodopa ( 18 F-dopa) uptake ( Fig. 1) [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], and histopathological studies have shown long-term, extensive synaptic reinnervation in the striatum [13,[20][21][22][23][24][25][26][27].…”

Medicina regenerativa con células madre adultas

“…No hay que olvidar que esta situación se aplica a enfermedades muy prevalentes y con gran impacto social, como el accidente cerebrovascular, la lesión cerebral y medular postraumática, o las enfermedades neurodegenerativas, para las que no existe actualmente alternativa de tratamiento curativo. El aparente fracaso del uso de injertos de células diferenciadas con capacidad de liberar neurotransmisores, fundamentalmente de mesencéfalo fetal en la enfermedad de Parkinson (EP) 45 , ha renovado el interés de la investigación con células troncales neurales (CTN). Aunque no existe evidencia para asegurar que la terapia celular con CTN es superior al uso de neuronas primarias en injertos fetales, su uso puede permitir la disponibilidad de un número elevado de células en distintos grados de diferenciación, y su manipulación in vitro, ambiental o genética, para mejorar su supervivencia, diferenciación, migración e integración 46 .…”