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REVIEW Potential cellular and regenerative approaches for the treatment of Parkinson’s disease
"... Abstract: Parkinson’s disease is most commonly treated with a range of pharmacotherapeutics, with the more recent introduction of surgical techniques including deep-brain stimulation. These have limited capabilities to improve symptoms of the disease in more advanced stages, thus new therapeutic str ..."
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Abstract: Parkinson’s disease is most commonly treated with a range of pharmacotherapeutics, with the more recent introduction of surgical techniques including deep-brain stimulation. These have limited capabilities to improve symptoms of the disease in more advanced stages, thus new therapeutic strategies including the use of viral vectors and stem cells are in development. Providing a continuous supply of dopamine to the striatum in an attempt to improve the treatment of motor symptoms using enzymes in the dopamine synthesis and machinery is one approach. Alternatively, there are tools which may serve to both protect and encourage outgrowth of surviving neurons using growth factors or to directly replace lost innervation by transplantation of primary tissue or stem cell-derived dopaminergic neurons. We summarize some of the potential therapeutic approaches and also consider the recent EU directives on practical aspects of handling viral vectors, cells and tissues, and in the running of clinical trials in Europe which impact on their development.
Cell Fate Analysis of Embryonic Ventral Mesencephalic Grafts in the 6-OHDA Model of Parkinson’s Disease
"... Evidence from carefully conducted open label clinical trials suggested that therapeutic benefit can be achieved by grafting fetal dopaminergic (DAergic) neurons derived from ventral mesencephalon (VM) into the denervated striatum of Parkinson’s disease (PD) patients. However, two double-blind trials ..."
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Evidence from carefully conducted open label clinical trials suggested that therapeutic benefit can be achieved by grafting fetal dopaminergic (DAergic) neurons derived from ventral mesencephalon (VM) into the denervated striatum of Parkinson’s disease (PD) patients. However, two double-blind trials generated negative results reporting deleterious side effects such as prominent dyskinesias. Heterogeneous composition of VM grafts is likely to account for suboptimal clinical efficacy. We consider that gene expression patterns of the VM tissue needs to be better understood by comparing the genetic signature of the surviving and functioning grafts with the cell suspensions used for transplantation. In addition, it is crucial to assess whether the grafted cells exhibit the DAergic phenotype of adult substantia nigra pars compacta (SNpc). To investigate this further, we used a GFP reporter mouse as source of VM tissue that enabled the detection and dissection of the grafts 6 weeks post implantation. A comparative gene expression analysis of the VM cell suspension and grafts revealed that VM grafts continue to differentiate post-implantation. In addition, implanted grafts showed a mature SNpc-like molecular DAergic phenotype with similar expression levels of TH, Vmat2 and Dat. However, by comparing gene expression of the adult SNpc with dissected grafts we detected a higher expression of progenitor markers in the grafts. Finally, when compared to the VM cell suspension, post-grafting there was a higher expression of markers inherent to glia and other neuronal populations. In summary, our data highlight the dynamic development of distinctive DAergic and non-DAergic
Signs of Degeneration in 12–22-Year Old Grafts of Mesencephalic Dopamine Neurons in Patients with Parkinson’s Disease
"... Abstract. We demonstrate that grafted human fetal mesencephalic neurons can survive and extend axons for 22 years in the brain of a patient with Parkinson’s disease (PD). In this patient, the overall survival and fiber outgrowth of the grafts were, however, relatively poor, which is consistent with ..."
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Abstract. We demonstrate that grafted human fetal mesencephalic neurons can survive and extend axons for 22 years in the brain of a patient with Parkinson’s disease (PD). In this patient, the overall survival and fiber outgrowth of the grafts were, however, relatively poor, which is consistent with the lack of significant clinical graft-induced benefit. We have compared the morphology of neurons in the 22-year old grafts with those in two younger grafts (16- and 12-year old), which were sequentially implanted in another PD patient. In the case with the 22-year-old transplant, a high proportion (up to 38%) of the grafted dopaminergic (pigment-granule containing) neurons do not express tyrosine hydroxylase and dopamine transporter and their perikarya appear atrophic. The proportion of pigmented neurons not expressing these markers is lower in the 12–16 year old grafts. Furthermore, in the 22-year-old graft, 49 % of the pigmented neurons display -synuclein immunoreactivity in the cell body and 1.2 % of them contain Lewy bodies. In conclusion, our results show that grafted dopaminergic neurons can survive for more than two decades. However, over time an increasing proportion of grafted neurons exhibit signs of degeneration.
