The limited clinical benefits obtained with fetal nigral transplantation to date coupled with the societal and logistic issues involved in the use of human embryonic tissue, has led to a search for alternate sources of dopaminergic cell types for transplantation in PD. As previously discussed, adrenomedullary tissue has been abandoned as patients did not maintain long-term benefit and the procedure was associated with considerable morbidity. Extra-adrenal chromaffin tissue has attracted some attention. The organ of Zuckerkandl is a paired organ located adjacent to the abdominal aorta which represents a source of GDNF (Bohn et al., 1982). Transplant of this tissue has been reported to induce functional improvement in Parkinsonian rats (Espejo et al., 2001). Autologous sympathetic ganglia cells have been tested in small groups of patients with advanced PD. In one study, patients were reported to have a decrease in "off" time (Nakao et al., 2001), while another found amelioration of bradykinesia and gait dysfunction in half of transplanted patients (Itakura et al., 1997). Transplantation of autologous carotid body cells improved motor function in Parkinsonian rodents and (Luquin et al., 1999; Toledo-Aral et al., 2003) were reported to provide some benefits to a small number of PD patients (Arjona et al., 2003). However, post-mortem studies demonstrated no evidence of graft integration into the brain nor evidence that they secreted dopamine. Carotid body tissue undergoes atrophy with increasing age and it has been suggested that any improvement seen in these experiments was due to the release of trophic factors and not from restoration of the nigrostriatal system (Toledo-Aral et al., 2003). None of these procedures has been studied in double-blind placebo-controlled trials.
Transplantation of porcine fetal nigral cells has been reported to provide some benefit in open label studies in PD patients (Schumacher et al., 2000). However; there were only a few surviving transplanted dopaminergic cells at post-mortem (Deacon et al., 1997), and no benefit was detected in double-blind studies (unpublished studies). Human retinal epithelial cells secrete levodopa, are relatively resistant to immune rejection and survive following transplantation when implanted attached to gelatin microcarriers (Spheramine®) (Subramanian et al., 2002). Spheramine transplantation has been reported to provide anti-Parkinson effects when transplanted into the striatum of the MPTP monkey and in open label trials in PD patients (Watts et al., 2003). No serious adverse events related to the microcarrier system have been noted and no patient has yet been reported with off-medication dyskinesia. A doubleblind placebo-controlled study to test this approach in PD patients is currently under way.
Most optimism for the treatment of PD with a cell-based therapy rests on stem cells as a source of dopamine neurons for transplantation, although there are still many hurdles that must be overcome. Stem cells are pluripotent cells that have the potential to differentiate into all of the different cell types of the body. Several types of stem cells have been studied: embryonic stem cells (ES cells), neural stem cells (NSCs) that are found within the fetal and adult brain, and primitive cells that are found in the bone marrow and umbilical cord. In the laboratory, ES cells are the most promising as approximately 50% spontaneously differentiate into a neuronal phenotype. ES cells are harvested from the inner cell membrane of the blastocyst and offer the potential of being expanded to provide a renewable source of dopamine neurons. Mouse ES cells have been shown to spontaneously differentiate into neurons following transplantation, with a few showing phenotypic features of dopamine neurons
(Bjorklund et al., 2002). The yield can be increased by inducing ES cells to differentiate into dopamine neurons while in culture using agents such as Nurr-1, trophic factors, sonic hedgehog, Bcl-XL, and ascorbate (Kim et al., 2003; Park et al., 2005). A higher yield of TH+ cells for transplantation can be accomplished by using a cell sorter to identify dopaminergic cells that have been transfected with a green fluorescent protein reporter (Yoshizaki et al., 2004). More recently, studies have demonstrated that human ES cells can also be induced to differentiate into dopamine neurons (Perrier et al., 2004). Transplanted dopamine neurons derived from ES cells have now been shown to be able to survive and to provide behavioral improvement in the 6-OHDA rat model (Bjorklund et al., 2002). Importantly, ES cells have also been reported to improve motor features and to increase striatal FD uptake on PET in MPTP-lesioned monkeys (Takagi et al., 2005).
Neural stem cells initially generated considerable enthusiasm because they already have a neuronal lineage, but results have been disappointing as they primarily differentiate into astroglia (Gage, 2000; Magavi and Macklis, 2001; Storch et al., 2004). A few cells spontaneously differentiate into dopamine pheno-types following transplantation (Yang et al., 2002), and they can be induced to differentiate into mid-brain dopaminergic neurons by exposure to agents such as cytokines and trophic factors (Carvey et al., 2001; Burnstein et al., 2004; Wang et al., 2004). Behavioral effects can be observed following transplantation into the rat model of PD, but only a few TH+ positive cells are found at post-mortem. Autologous stem cells derived from the umbilical cord or bone marrow are also of great interest because they can avoid the immunological and societal issues associated with embryonic stem cells. However, they also default to glial cells and to date it has proven difficult to generate large numbers of dopamine neurons suitable for transplantation. In vitro treatment with GDNF increase TH positivity in bone marrow stromal cells, and following transplantation they have been shown to produce behavioral improvement in the 6-OHDA rat (Dezawa et al., 2004).
Stem cells offer the theoretical advantage of providing a source of virtually unlimited and optimized dopamine neurons for transplantation in PD. There are however many issues that remain to be resolved. It has not yet proven easy to routinely generate large numbers of dopamine neurons for transplantation, and the optimal type of stem cell and method of inducing them to differentiate into dopamine neurons remain to be determined. Studies in models of PD show limited cell survival and do not provide benefits superior to fetal nigral transplants, which to date have not been confirmed to yield significant results in PD patients in double-blind trials. The adverse event profile must be defined. Transplantation of pluripotential stem cells carries with it the risk of unregulated growth and tumor formation. Indeed, 5 of 17 rats transplanted with stem cells had teratomas at post-mortem examination (Bjorklund et al., 2002). Studies will also have to be conducted to determine if stem cells are associated with off-medication dyskinesia, and if so how to prevent them. In addition, extensive laboratory testing will have to be performed to exclude unanticipated side-effects, to the extent possible, prior to entering into clinical trial. Stem cells will also need to be proven to be more effective than just pharmacologic replacement of lost dopamine. Finally, it is by no means assured that even complete and physiologic restoration of the nigrostriatal dopamine system will eliminate disability in PD patients caused by degeneration of non-dopaminergic neurons (see below).
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