Emerging restorative treatments for Parkinson's disease
Introduction
Almost 20 years ago, the first successful cell transplantation trials in Parkinson's disease (PD) patients promoted the view that the damaged brain can be repaired by replacing lost neurons (Lindvall et al., 1990). Over the last decade, new discoveries have indicated that the adult human brain has the potential to generate its own new neurons, and that therefore the adult brain is much more plastic than was initially believed (Curtis et al., 2007, Eriksson et al., 1998). Furthermore, the concomitant exploration of several growth factors with neurotrophic capacity, and demonstration that they can promote regrowth of damaged neural connections, have reinforced the view that the adult brain may be amenable to restorative therapies. The idea that adult neurogenesis can be controlled and manipulated to restore lost dopaminergic neurons in the brains of PD patients has attracted recent attention. Meanwhile, another aspect of stem cell research has focused on regenerative medicine, based on attempting to restore lost cells and tissues in the human body by grafting stem cells or their progeny.
The future outlook for existing PD therapies has been reviewed by Singh et al. (2007). Current therapies for PD are primarily based on pharmacological replacement of lost striatal dopamine. Dopamine replacement can be achieved through administration of the dopamine precursor l-dopa, direct activation of the dopamine receptor by agonists, or by augmentation of the remaining dopaminergic neurotransmission through inhibition of dopamine-degrading enzymes. These approaches have achieved remarkable relief of PD symptoms. However, none lead to complete dopamine restoration or marked neuroprotection of the remaining dopaminergic neurons, and long-term drug administration can result in side effects related to disease progression. In advanced disease, the vast majority of patients experience fluctuations in response to medication, a phenomenon known as the “on–off” effect. Patients are able to move during the “on” period, whereas they are immobile during the “off” period. After a few years of drug treatment, most patients exhibit multiple “off” periods every day. In addition, patients may suffer from l-dopa-induced dyskinesias, typically during “on” periods or when they transition from “on” to “off”. Patients with this complication can be successfully treated with deep brain stimulation, mainly targeting the subthalamic nucleus. These operations can partially normalize abnormal neural activity in the subthalamic-pallidum connections, which drives some of the symptoms.
Regardless of the known side effects, pharmacological dopamine replacement remains an important therapy, which illustrates the fundamental centrality of the nigrostriatal dopamine system to the symptomatology of PD. Indeed, much would be gained if these neurons could be restored or replaced in the brains of PD patients. The successful transplantation of embryonic mesencephalic cells into the striatum of patients with PD in the late 1980s raised hopes that it may be possible not only to halt progression, but also to actually reverse the disease. The shortage of suitable embryonic donor tissue is a major limiting factor that precludes use of this cell therapy as a general therapy for PD. In addition, results from animal studies indicate that only roughly 10% of these cells survive transplantation (Brundin et al., 2000a). Based on this considerable cell death, and the fact that only few dopaminergic precursors are present in the donor tissue to begin with, enrichment of dopaminergic neurons prior to transplantation would be valuable. Thus, there is an unmet need for a means of generating a large pool of dopaminergic precursors or neurons for use in transplantation procedures.
In this review, we discuss various approaches to restorative therapy in PD (Fig. 1). Some, such as the viral vector-mediated delivery of dopamine-synthesizing enzymes, are based on restoring the neurochemistry of the striatum (Carlsson et al., 2007, Singh et al., 2007). However, in this review we do not discuss attempts to directly restore neurotransmitter-synthesizing enzymes further. Instead we focus on therapies that promote structural and cellular restoration of the basal ganglia in PD patients. These therapies are primarily applicable to patients in which conventional pharmacotherapy has begun to fail. We describe them in order of the PD stages to which they are relevant, as the disease progresses from moderate to severe. Hence, we will first discuss neuroprotection/restoration of the diseased nigrostriatal dopamine system by growth factor delivery, particularly delivery of glial cell line-derived neurotrophic factor (GDNF). When the diseased nigral dopaminergic neurons in the PD brain are beyond rescue, cell transplantation is an option to restore lost neurons. In the next section, we will therefore cover cell transplantation and briefly describe key animal experiments, as well as available clinical data regarding fetal cell transplantation. In the subsequent section, we will describe the developmental biology of dopaminergic neurons, and the characteristics of different stem cells used to generate dopaminergic neurons for transplantation purposes. We focus on the various approaches utilized to differentiate these stem cells into dopaminergic neurons. In the final section, we will cover neurogenesis in the adult brain as a hypothetical strategy to restore dopaminergic neurons in PD patients.
Section snippets
Growth factor delivery in the brain
In this section, we review the use of several well-known growth factors used in both preclinical studies and clinical trials. We pay special attention to GDNF and its protective and restorative effect on the dopamine-depleted striatum. This molecule has been studied extensively in experimental models of PD for more than a decade. First, we provide an overview of the beneficial effects of growth factors on degenerating dopaminergic neurons. Further, we discuss various strategies for growth
Cell transplantation therapy for Parkinson's disease
The successful transplantation of immature dopaminergic neurons in animal models of PD spurred clinical trials in patients starting in the mid-1980s. In a short section, we describe some key animal experiments relevant to clinical trials, and recent developments regarding the grafting of stem cell-derived dopaminergic neurons. We then briefly describe results obtained in open-label clinical trials during the 1990s, and compare them to those derived from two major controlled trials that have
Stem cells as a source for dopamine cell transplantation
For a successful cell-based therapy for PD, knowledge about the developmental stage and identity of the transplanted cells are crucial to obtain optimal integration and survival of the graft in the host brain. In the initial section, we introduce the relevant developmental biology, i.e. how a stem cell in the midbrain can become a dopaminergic neuron. In the following sections we describe different sources of stem cells that might be used to generate dopaminergic neurons, i.e. neural and
Neurogenesis in the human brain
During the last decade, neurogenesis has been confirmed in two regions in the human brain: the hippocampal subgranular zone (SGZ) in the dentate gyrus and the subventricular zone (SVZ) lining the lateral ventricles (Curtis et al., 2007, Eriksson et al., 1998). These two neurogenic regions have been extensively studied in the rodent brains. The neuroblasts originating from the SVZ migrate via the rostral migratory stream to the olfactory bulb where they mature into region specific neurons and
Conclusion
In this review, we highlight the varying aspects of both experimental research and clinical approaches currently being undertaken for restorative treatment of PD. Some of these therapies, when eventually developed to their full potential, may not only halt the progression of the disease, but also give the patient back functions already lost. The most clinically driven approach currently being investigated is the delivery of growth factors from the GDNF family. Many approaches are being tested
Acknowledgements
Swedish Research Council, Tore Nilson's Foundation, PROMEMORIA (EU 6th FP), NeuroNe (EU 6th FP), Magnus Bergvall's Foundation, STEMS (EU 6th FP), Royal Physiographic Society, Kock's Foundations, Memory of Lars Hierta's Foundation, Torsten och Ragnar Söderberg's Foundations, Foundation Olle Engkvist Byggmästare, King Gustaf V's and Queen Victoria's Stiftelse, Swedish Brain Foundation, and Parkinson's Disease Society UK.
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