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BMC Medicine (3)
Lindvall, Olle (1)
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Clinical application of stem cell therapy in Parkinson's disease
Cell replacement therapies in Parkinson's disease (PD) aim to provide long-lasting relief of patients' symptoms. Previous clinical trials using transplantation of human fetal ventral mesencephalic (hfVM) tissue in the striata of PD patients have provided proof-of-principle that such grafts can restore striatal dopaminergic (DA-ergic) function. The transplants survive, reinnervate the striatum, and generate adequate symptomatic relief in some patients for more than a decade following operation. However, the initial clinical trials lacked homogeneity of outcomes and were hindered by the development of troublesome graft-induced dyskinesias in a subgroup of patients. Although recent knowledge has provided insights for overcoming these obstacles, it is unlikely that transplantation of hfVM tissue will become routine treatment for PD owing to problems with tissue availability and standardization of the grafts. The main focus now is on producing DA-ergic neuroblasts for transplantation from stem cells (SCs). There is a range of emerging sources of SCs for generating a DA-ergic fate in vitro. However, the translation of these efforts in vivo currently lacks efficacy and sustainability. A successful, clinically competitive SC therapy in PD needs to produce long-lasting symptomatic relief without side effects while counteracting PD progression.
Optimizing functional imaging protocols for assessing the outcome of fetal cell transplantation in Parkinson's disease
Clinical trials aiming to assess the safety and efficacy of fetal cell transplantation in Parkinson's disease rely on the hypothesis that the grafted tissue will survive and grow, restore striatal dopaminergic neurotransmission, improve the connectivity between striatum, thalamus and cortex and, thereby, produce long-lasting clinical improvement while avoiding the development of adverse effects. Although transplantation of human fetal ventral mesencephalic tissue has been reported as one of the most effective reparative therapies in Parkinson's disease patients to date, different studies have shown inconsistent results causing a paucity of new trials over the last decade. However, during this period, functional imaging alongside other scientific developments from clinical observations and animal work has significantly aided in understanding the mechanisms responsible for the success or failure of grafting human fetal tissue. Recent advances in functional imaging including both positron emission tomography and functional magnetic resonance imaging could be proven useful in vivo tools for the development and assessment of new clinically competitive trials. In this commentary we discuss how an optimized functional imaging protocol could assist new clinical trials using fetal cell transplantation in Parkinson's disease.
Dyskinesias after neural transplantation in Parkinson's disease: what do we know and what is next?
Since the 1980 s, when cell transplantation into the brain as a cure for Parkinson's disease hit the headlines, several patients with Parkinson's disease have received transplantation of cells from aborted fetuses with the aim of replacing the dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced dyskinesias could be related to fiber outgrowth from the graft causing increased dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced dyskinesias could include the composition of the cell suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with Parkinson's disease who exhibited major motor recovery after transplantation with fetal mesencephalic tissue but later developed graft-induced dyskinesias. Moreover, the dyskinesias were significantly attenuated by administration of a serotonin agonist, which activates the inhibitory serotonin autoreceptors and attenuates transmitter release from serotonergic neurons, indicating that graft-induced dyskinesias were caused by the dense serotonergic innervation engaging in false transmitter release. Here the implications of the recent findings for the development of new human trials testing the safety and efficacy of cell transplantation in patients with Parkinson's disease are discussed.
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