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- Björklund, Tomas, et al.
(författare)
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Gene therapy for dopamine replacement.
- 2010
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Ingår i: Progress in Brain Research. - 1875-7855. ; 184, s. 221-235
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Forskningsöversikt (refereegranskat)abstract
- Dopamine replacement for Parkinson's disease (PD) have seen three major iterations of improvements since the introduction of l-3,4-dihydroxyphenylalanine (l-DOPA) pharmacotherapy: dopamine receptor agonists, ex vivo gene transfer for cell transplantation and most recently in vivo gene therapy. In this chapter, we describe the principles behind viral vector-mediated enzyme replacement in PD. We focus on the enzymes involved in the dopamine synthesis and their internal regulation, the early experimental work on gene therapy using different viral vector types and selection of transgenes, and finally discuss the recently completed early phase clinical trials in PD patients.
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- Brundin, Patrik, et al.
(författare)
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Neural grafting in Parkinson's disease: problems and possibilities
- 2010
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Ingår i: Progress in Brain Research. - 1875-7855. ; 184, s. 265-294
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Forskningsöversikt (refereegranskat)abstract
- Neural transplantation has emerged as a possible therapy for Parkinson's disease (PD). Clinical studies performed during the 1990s, where dopaminergic neurons derived from the human embryonic brain were transplanted into striatum of patients with PD, provided proof-of-principle that long-lasting therapeutic benefits can be achieved. Subsequent studies, in particular two that followed a double-blind, sham surgery, placebo-control design, showed variable and mostly negative results. They also revealed that some patients develop involuntary movements, so called graft-induced dyskinesias, as side effects. Thus, while nigral transplants clearly work well in select PD cases, the technique needs refinement before it can successfully be performed in a large series of patients. In this review, we describe the clinical neural transplantation trials in PD and the likely importance of factors such as patient selection, trial design, preparation of the donor tissue, and surgical techniques for successful outcome and avoiding unwanted side effects. We also highlight that it was recently found that neuropathological signs typical for PD can appear inside some of the grafted neurons over a decade after surgery. Finally, we discuss future possibilities offered by stem cells as potential sources of dopamine neurons that can be used for transplantation in PD.
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| 7. |
- Brundin, Patrik, et al.
(författare)
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Neuropathology in transplants in Parkinson's disease: Implications for disease pathogenesis and the future of cell therapy.
- 2012
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Ingår i: Progress in Brain Research. - 1875-7855. ; 200, s. 221-241
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Tidskriftsartikel (refereegranskat)abstract
- Neural transplantation is over a century old, but the modern era encompasses only the last 30-40 years. For most of this time period, research has focused on reversing disability engendered by neurologic disease and brain damage. Only recently was it recognized that the underlying neurological disease itself might negatively impact the grafted neurons. We have found that a subset of neurons within embryonic neural grafts that survive more than 10 years in Parkinson patients display Lewy bodies, a classical feature of Parkinson's disease neuropathology. Additionally, the grafted cells placed in the Parkinson's disease brain eventually downregulate the expression of dopamine transporter and tyrosine hydroxylase in a manner similar to what is seen in the substantia nigra dopamine neurons that are degenerating due to the disease. We discuss these findings in terms of how they might improve our understanding of Parkinson's disease pathogenesis and the effects they may have on the future of neural cell replacement strategies.
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- Cenci Nilsson, Angela, et al.
(författare)
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Maladaptive striatal plasticity in L-DOPA-induced dyskinesia.
- 2010
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Ingår i: Progress in Brain Research. - 1875-7855. ; 183, s. 209-233
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Forskningsöversikt (refereegranskat)abstract
- Dopamine (DA) replacement therapy with l-DOPA remains the most effective treatment for Parkinson's disease, but causes dyskinesia (abnormal involuntary movements) in the vast majority of the patients. The basic mechanisms of l-DOPA-induced dyskinesia (LID) have become the object of intense research focusing on neurochemical and molecular adaptations in the striatum. Here we review this vast literature and highlight trends that converge into a unifying pathophysiological interpretation. We propose that the core molecular alteration of striatal neurons in LID consists in an inability to turn down supersensitive signaling responses downstream of DA D1 receptors (where supersensitivity is primarily caused by DA denervation). The sustained activation of intracellular signaling pathways induced by each dose of l-DOPA leads to abnormal cellular plasticity and high bioenergetic expenditure. The over-exploitation of signaling pathways and energy reserves during treatment impairs the ability of striatal neurons to dynamically gate cortically driven motor commands. LID thus exemplifies a disorder where 'too much' molecular plasticity leads to plasticity failure in the striatum.
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| 9. |
- Cooper, Oliver, et al.
(författare)
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Characterization and criteria of embryonic stem and induced pluripotent stem cells for a dopamine replacement therapy
- 2012
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Ingår i: Progress in Brain Research. - 1875-7855. ; 200, s. 76-265
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Tidskriftsartikel (refereegranskat)abstract
- Human pluripotent stem cells provide new choices for sources of A9-type dopaminergic (DA) neurons in clinical trials of neural transplantation for patients with Parkinson's disease (PD). For example, "self" and HLA-matched A9 DA neurons may improve the patient-to-patient variability observed in previous clinical trials using fetal DA neurons and obviate the need for long-term immunosuppression in the patient. Normal chromosomal structure and minimal somatic mutations in pluripotent stem cells are necessary criteria for assuring the safe and reproducible transplantation of differentiated DA neurons into patients with PD in clinical trials. However, with these new choices of cell source, the application of pluripotency assays as criteria to ensure pluripotent stem cell quality becomes less relevant. New more relevant standards of quality control, assurance, and function are required. We suggest that quality assurance measures for pluripotent stem cells need to focus upon readouts for authentic midbrain DA neurons, their integration and growth using in vivo assays, and their long-term functional stability.
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- Dunnett, Stephen B, et al.
(författare)
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Introduction (Part I)
- 2012
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Ingår i: Functional Neural Transplantation III : Primary and stem cell therapies for brain repair. Part 1 - Primary and stem cell therapies for brain repair. Part 1. - 0079-6123. - 9780444595751 ; 200, s. 3-5
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