Dyskinesias following neural transplantation in Parkinson's disease

Hagell, Peter; Piccini, Paola; Björklund, Anders; Brundin, Patrik; Rehncrona, Stig; Widner, Håkan; Crabb, Lesley; Pavese, Nicola; Oertel, Wolfgang H.; Quinn, Niall; Brooks, David J.; Lindvall, Olle

doi:10.1038/nn863

Cited by 410 publications

(301 citation statements)

References 11 publications

(7 reference statements)

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Elsworth

Redmond

Léránth

et al. 2008

Experimental Neurology

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Neural transplantation offers the potential of treating Parkinson's disease by grafting fetal dopamine neurons to depleted regions of the brain. However, clinical studies of neural grafting in Parkinson's disease have produced only modest improvements. One of the main reasons for this is the low survival rate of transplanted neurons. The inadequate supply of critical neurotrophic factors in the adult brain is likely to be a major cause of early cell death and restricted outgrowth of fetal grafts placed into the mature striatum. Glial derived neurotrophic factor (GDNF) is a potent neurotrophic factor that is crucial to the survival, outgrowth and maintenance of dopamine neurons, and so is a candidate for protecting grafted fetal dopamine neurons in the adult brain. We found that implantation of adenoassociated virus type 2 encoding GDNF (AAV2-GDNF) in the normal monkey caudate nucleus induced over-expression of GDNF that persisted for at least 6 months after injection. In a 6-month within-animal controlled study, AAV2-GDNF enhanced the survival of fetal dopamine neurons by 4-fold, and increased the outgrowth of grafted fetal dopamine neurons by almost 3-fold in the caudate nucleus of MPTP-treated monkeys, compared with control grafts in the other caudate nucleus. Thus, the addition of GDNF gene therapy to neural transplantation may be a useful strategy to improve treatment for Parkinson's disease.

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Section: Discussionmentioning

confidence: 99%

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

Elsworth

Redmond

Léránth

et al. 2008

Experimental Neurology

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“…The appearance of GIDs was first observed in the Denver/ Columbia trial [6], and subsequently they have also been reported in some of the patients in the Swedish program [36] and in the Tampa/Mount Sinai trial [14]. This side effect came as a surprise, because none of the pre-clinical studies in rodent and primate models of PD have observed any adverse responses of this type.…”

Section: Adverse Effects Are Few With Dopaminergic Grafts Except Dysmentioning

confidence: 96%

Cell Therapeutics in Parkinson's Disease

Lindvall

Björklund

2011

Neurotherapeutics

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The main pathology underlying motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process longterm after implantation. Mechanisms underlying graftinduced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

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“…Dyskinesias have appeared in transplant recipients who had L-DOPA-induced dyskinesias prior to transplant [3,5,7,9,[48][49][50][51][52]. In nearly all patients who have responded to transplants, there is an initial period of increased dyskinesias, which resolves as drug doses are reduced.…”

Section: Transplants That Replace the Need For L-dopa Can Replicate Dmentioning

confidence: 99%

Dopamine Cell Transplantation for Parkinson's Disease: The Importance of Controlled Clinical Trials

2011

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Dyskinesias following neural transplantation in Parkinson's disease

Cited by 410 publications

References 11 publications

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

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

Cell Therapeutics in Parkinson's Disease

Dopamine Cell Transplantation for Parkinson's Disease: The Importance of Controlled Clinical Trials

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