Biodrugs 2004; 18 (3): 141-153 1173-8804/04/0003-0141/$31.00/0
CURRENT OPINION
© 2004 Adis Data Information BV. All rights reserved.
Is There a Future for Neural Transplantation? Timothy P. Harrower1,2 and Roger A. Barker1,2 1 2
Cambridge Centre for Brain Repair, Forvie Site, Cambridge, UK Department of Neurology, Addenbrooke’s Hospital, Cambridge, UK
Abstract
Traditionally neural transplantation has had as its central tenet the replacement of missing neurons that have been lost because of neurodegenerative processes, as exemplified by diseases such as Parkinson disease (PD). However, the effectiveness and widespread application of this approach clinically has been limited, primarily because of the poor donor supply of human fetal neural tissue and the incomplete neurobiological understanding of the circuit reconstruction required to normalize function in these diseases. So, in PD the progress from promising neural transplantation in animal models to proof-of-principle, open-labeled clinical transplants, to randomized, placebo-controlled studies of neural transplantation has not been straightforward. The emergence of previously undescribed adverse effects and lack of significant functional advantage in recent clinical studies has been disappointing and has served to cast a new, and perhaps more realistic, perspective on this treatment approach. In fact, there have been calls by some involved in neural transplantation to return to the drawing board before pressing on with further clinical trials, and the return to basic experimentation. This therefore precipitates the question – is there a future for neural transplantation? It is important to remember that there are a number of possible explanations for the disappointing results from the recent clinical trials in PD, ranging from the mode of transplantation to patient selection. Nevertheless, almost irrespective of these reasons for the current trial results, there have always been significant practical and ethical problems with using human fetal tissue, and so a number of alternative cell sources have been investigated. These alternative sources include stem cells, which are attractive for cell-based therapies because of their potential ease of isolation, propagation and manipulation, and their ability in some cases to migrate to areas of pathology and differentiate into specific and appropriate cell types. Furthermore, the availability of stem cells derived from non-embryonic sources (e.g. adult stem cells derived from the sub-ventricular zone) has removed some of the ethical limitations associated with the use of embryonic human tissue. These potentially beneficial aspects of stem cells means that there is a future for neural transplantation as a means of treating patients with a range of neurological disorders, although whether this will ever translate into a truly effective, widely available therapy remains unknown.
Neural transplantation classically involves the replacement of cells lost in the CNS as a result of a disease process. The most reliable method to date involves cells derived from the developing fetal brain, which are then stereotactically placed into a specific region in the diseased brain. This region typically represents the core pathological event, although it is becoming clear that there is diffuse pathology in most neurological disorders and so a different view is emerging of what is required by any transplantable source of cells. Nevertheless, for the purposes of this review we have
defined neural transplantation as the use of cell-based therapies to influence the nervous system by either: (i) repair of damaged regions; (ii) replacement of lost cells; or (iii) delivery of various molecular agents (to act as neurotransmitters, neuromodulators, or antimitotic agents). This approach will focus on Parkinson disease (PD) as this is the condition for which the most work has been done and thus data is available both experimentally and clinically. We will do this by concentrating on the current status of clinical trials in PD using
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human fetal allografts before discussing alternative sources of cells such as stem cells. 1. Clinical Neural Transplantation for Parkinson Disease (PD) Neural transplantation is best known for its use in PD, with at least 300 patients worldwide having received transplants of primary human fetal dopaminergic tissue. In PD, the primary pathological event targets the nigral dopaminergic neurons, which project to the caudate nucleus and putamen. This loss of neurons gives rise to the cardinal symptoms and signs of PD, namely bradykinesia (slow movements) or akinesia (lack of movement most noticeable with poverty of hand movement when walking), rigidity, and rest tremor, although the latter sign may actually have its origins in non-dopaminergic areas involved in the disease process. Nevertheless, it is the replacement of the dopaminergic cells which forms the rationale for neural transplantation programs in PD, although it is recognized that patients with PD have a range of other deficits including nonmotor ones, which probably have a pathological basis outside of this transmitter system. 1.1 Current Treatment Options for PD
In the early stages, many of the motor symptoms and signs of PD can be treated effectively with drugs targeting the dopaminergic pathway such as dopamine agonists and levodopa. However, with disease progression there is a need to increase the dosage of dopamine replacement therapy and, with time, adverse effects start to emerge including drug-induced dyskinesias, which makes the management of such patients more complex and often unpredictable. As a result, at this stage of the disease alternative strategies are needed and have included the use of continuous dopaminergic agonist infusion and/or neurosurgery.[1-7] However, an alternative and promising approach which has been trialed recently involves the use of neurotrophic factors – in particular Glial cell line-derived neurotrophic factor (GDNF) – to rescue remaining dopaminergic cells.[8] This agent has been the subject of two phase I safety trials in which it was directly infused into the brains of PD patients. In one study GDNF was infused into the ventricles of PD patients and in another directly into the brain parenchyma. The first of these was a randomized, double-blind study involving 50 patients with relatively advanced disease. GDNF administered by this route was biologically active, as evidenced by an array of adverse events (nausea, anorexia, vomit© 2004 Adis Data Information BV. All rights reserved.
ing, weight loss, paraesthesia, and hyponatremia) but did not improve the clinical state, possibly because it did not penetrate into the target tissues, the striatum and substantia nigra.[9] Thus, the second, much smaller study involved GDNF being infused directly into the putamen of five PD patients. Functional imaging at 18 months after the infusion using positron emission tomography (PET) scans, showed a 28% increase in putamen dopamine storage, and clinically, a 61% improvement in activities of daily living with a 64% reduction in medication-induced dyskinesias.[10] 1.2 Current Status of Neurotransplantation for PD
A similar restorative approach to this rescue of dopaminergic cells by GDNF is therefore their replacement by neural transplantation.[11-13] Based on a sound experimental background,[14] pilot studies in patients began to be undertaken in the second half of the 1980s. These studies confirmed that lasting clinical benefits of up to 14 years are possible using this approach, and that these benefits are directly due to the grafted tissue as evidenced through functional PET studies.[15,16] Overall, the data from these ongoing, open label studies with moderately severe patients show motor score improvement of up to 40% in the Unified Parkinson’s Disease Rating Scale (UPDRS)[17-20] with a striatal dopamine uptake increase of up to 60–70% using 18F-dopa PET.[21] Furthermore, in these studies there was little evidence for the induction of major dyskinesias, and in fact there was improved duration of time in the on state without dyskinesias.[17,19,20] However, because these studies were open-labeled and subject to bias, it was felt necessary to perform randomized, double-blind, placebo-controlled trials using human fetal mesencephalic tissue. The results of two such trials have been published, with the placebo limb having burr hole surgery with no breach of the dura and no graft placements. In the first of these studies, Freed et al.[22] reported the outcome measures at one year after transplantation. Using a subjective global rating scale, no overall improvement was demonstrated, although, in the subgroup of patients under 60 years of age, a significant improvement was observed compared with the placebo group. However, the functional benefit reported at one year follow up may represent an underestimate of graft function, as many of the patients have reported ongoing clinical improvement at 2–3 years after transplantation.[23] Of concern, however, was the first report of levodopa-independent dyskinesias, which occurred in 15% of patients and the origin of which remains obscure. In the second trial, Olanow et al.[24] reported no overall improvement following neural transplantation, although a subgroup of patients with less severe disease did appear to imBiodrugs 2004; 18 (3)
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Cell source? Stem cells Xenogeneic cells Genetically engineered
37˚C Stereotactic implantation into the host brain, using a microsyringe
Hibernation for up to 8 days 4˚C Nature of cells to be transplanted? Single purified cell population Undifferentiated multipotential stem cells Partially differentiated cells Population of a specific cell mix e.g. neurons 50% astrocytes 30% oligodendrocytes 20%
Enxymatic digestion and mechanical trituration Enzymatic digestion to produce a single cell suspension
Lateral aspect Which patients? Young/old Early/advanced disease
Coronal aspect Which anatomical site? To reduce adverse effects To enhance function
Immunosuppression?
Fig. 1. Outline of neural transplantation as it is traditionally undertaken and the questions that have been generated from randomized, double-blind, placebo-controlled studies. Cells isolated from the developing fetal brain are processed to produce a single suspension, which is stereotactically injected into an appropriate site in the CNS. However, recently published randomized, double-blind, placebo-controlled trials in patients with Parkinson disease have produced limited clinical benefits and adverse effects, suggesting five main questions which need to be addressed before further large scale trials are undertaken again.
prove. Furthermore, in this study more than 50% of the patients developing dyskinesias which were only partially levodopa-dependent (i.e. removal of levodopa for extended periods aborted these dyskinesias). The reason for this is not known but it is important to note that clinical studies have by and large targeted severely affected PD patients. In other words, stratification based on disease severity showed a significant treatment effect in the patients with milder disease, but not in those more severely affected. The reason for the differing outcomes in open label versus randomized, controlled studies is not known but may relate to the tissue preparation (cultured strands of neural tissue [Freed et al.[22]] as opposed to freshly prepared ventral mesencephalon), state of tissue (tissue pieces[24] and tissue strands[22]) versus single cell suspensions and degree of immunosuppression. In addition, patient selection has differed, with the latter, double-blind studies tending to recruit more advanced patients than the original openlabeled studies. Thus, direct comparisons between the original open-labeled studies should not be made, and the double-blind © 2004 Adis Data Information BV. All rights reserved.
studies, whilst not invalidating any of the initial findings derived from the open-label studies, nevertheless raise the following issues that require further investigation (figure 1). 1. The supply of donor tissue. Ethical and logistic reasons currently limit the use of human fetal neural tissue. Practically, harvesting adequate tissue for transplant programs where at least four to seven donors are required per side of the brain for treatment of PD is extremely difficult considering the limited time between harvesting and grafting, even using hibernation media.[25] Furthermore, the current move to medical, rather than surgical, termination of pregnancy has also decreased the tissue available for grafting, as medically induced terminations of pregnancy preclude any harvesting of viable tissue. 2. The nature of the donor material. The isolation and preservation of the cells that make up the donor cell population needs optimization such that adequate quantities are available to produce worthwhile functional improvement without significant adverse effects. In the case of PD, this involves harvesting or deriving adequate numbers of dopamine neurons, as well as characterizing the identiBiodrugs 2004; 18 (3)
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ty of the other cells that are grafted if the cell population is not of a pure single type.
2. Cells for Neural Transplantation
3. Graft placement. The exact site(s) where the cells are implanted needs to be addressed to ensure safe and effective transplantation without adverse effects. For example, uneven transplantation of tissue or placement into the ventral striatum may have led to some of the dyskinetic adverse effects seen in some of the PD fetal neural transplant trials. Recent 18F-dopa PET studies in early PD suggest the failure of compensatory the nigropallidal dopamine pathway to the internal globus pallidus (Gpi) but not to the external globus pallidus (Gpe) coincided with the appearance of drug induced dyskinesias.[26] Thus, when planning the implantation site for fetal dopaminergic tissue, this needs to be taken into account and it suggests that dopaminergic re-innervation of this pathway should be considered. Indeed, it may even be necessary to tailor the transplantation for each patient to optimize the effect of the transplant and to reduce adverse effects.
2.1 Criteria that Cells Should Possess for
4. Patient selection. The phenotype and disease stage of patients who will gain maximum benefit needs to be defined. Presently, the therapy has largely targeted end-stage disease where patients have significant problems with their condition, and this includes druginduced dyskinesia. 5. Use of immunosuppression. Most of the initial open-labeled studies used standard triple therapy immunosuppression, whilst the study by Freed and colleagues[22] used no immunosuppression, and Olanow[27] used only low-dose cyclosporine (ciclosporin) monotherapy as immunosuppression for 6 months. It is not clear whether allografted neural tissue requires immunosuppression for optimal survival and whether the use of more rigorous immunosuppression in open-labeled studies contributed to better outcomes compared with the double-blind studies. Whilst some of these issues can be addressed in the laboratory, questions of patient selection and optimal sites of implantation are difficult to answer using current animal models. Although animal models are helpful in terms of defining basic basal ganglia pathology and representing circuitry, they are not sufficiently defined and complex enough to represent the gradual progression of the neurodegeneration that occurs in patients with PD, although this may change with the development of transgenic models of PD or viral delivery of mutant toxic proteins.[28] Whilst these issues need to be resolved before further trials can be planned, there is a very real problem of tissue availability. As the search for alternative cell sources is underway it is useful to consider what will be required of this cell source and what would be considered as additional beneficial properties. © 2004 Adis Data Information BV. All rights reserved.
Neural Transplantation
In all cases the tissue should ideally have the following characteristics: • guaranteed reliable viability and homogeneity, and be free of infective risk and derived from an ethically acceptable source; • possess no risk of malignant transformation (or least as much risk as naturally occurring tissue), i.e. they should be as genetically stable as the healthy tissue; • survive in the host long term and be immune from the underlying disease process; • generate sufficient numbers of cells for grafting and so be able to survive the preparation process with appropriate differentiation and circuit reconstruction; • provide long-lasting functional benefit without significant adverse effects. Desirable characteristics that would allow for cell-based therapy to be extended to other neurological disorders include: • flexible and/or ‘on demand’ supply; • lack of immunogenicity; • the ability to migrate through the body or CNS to areas of pathology, with appropriate differentiation (especially important in diseases where pathology is dispersed in the CNS axis); and • reconstruction of host circuitry to normal. 2.2 Alternative Sources of Cells for Neural Transplantation
Given the criteria in section 2.1, the two most investigated alternative sources of cells are stem cells and cells from nonhuman sources, i.e. xenografts, although a variety of other cell sources have been investigated including genetically modified cell lines and ex vivo gene transfer to cells prior to transplantation. However, a discussion of such cells is beyond the scope of this review and such genetic modification is not discussed in detail here. 2.2.1 Cells from Non-Human Sources: the Pig?
To address the shortage of organs for clinical transplantation, research into the use of the pig as a source of such tissue is advanced and currently steps are underway to make them available for clinical transplantation programs. This transplantation across the species barrier is termed xenotransplantation (as opposed to allotransplantation, which is transplantation of organs within the Biodrugs 2004; 18 (3)
Is There a Future for Neural Transplantation?
same species) and has as its greatest strength the ability to overcome donor shortage, as pigs are easily bred. However, significant problems with rejection and theoretical infection risks have prevented this approach from being a clinical reality. The theoretical risk of transmission of porcine endogenous retroviruses (PERV) has led to many countries, including the UK, imposing a moratorium on the clinical application of xenotransplantation. Despite this, the possibility of overcoming the donor shortage using porcine tissue has meant that ongoing research continues. Scientifically, one of the most immediate problems limiting xenotransplantation is immune-mediated rejection, and thus numerous genetically engineered pig lines have been generated to reduce this. Indeed, through using a combination of genetically modified pig tissues and immunosuppression, it is possible that xenograft rejection could be constrained.[29-33] Therefore, a natural extension of these developments in organ xenografting is the use of porcine neurons for neural transplantation. The relative immune privilege of the brain and the use of single cell suspensions rather than vascularized whole organs substantially reduces the danger of xenograft rejection. Furthermore, the large litter sizes ensure that sufficient tissue is available from each pregnancy for grafting into patients. Embryonic porcine neural tissue when xenografted into rats produces neurite extension,[34] which can transverse the nigrostriatal pathway and form synapses.[35] In contrast, there is limited fiber extension from equivalent allografted rat ventral mesencephalic grafts[36] which suggests that fiber extension using xenografted tissue may be superior to allografted neural tissue.[35,37-39] Further support for this view comes from a study by Wictorin et al.[38] In this study, neuroblasts from the developing ventral mesencephalon of 6- to 8-week-old embryos implanted at different sites along the nigrostriatal pathway in adult rats (previously subjected to a dopaminergic lesion) showed a remarkable ability to extend axons along the trajectories of the nigrostriatal and mesolimbocortical pathways to reach and innervate the principal striatal and limbic target areas in the forebrain.[38] Therefore, circuit reconstruction is not only possible with neural xenografts but is also capable of ameliorating deficits such as drug-induced rotation in the 6-hydroxydopamine model of PD.[40,41] The possible neurobiological explanation for this superior axonal growth with xenografts may relate to the environment that exists in the CNS, which is predominantly non-permissive to allograft fiber extension but not xenografted neurons.[42-44] Alternatively, the longer gestational period and greater size of the pig and human brain may explain the described phenomena in the much smaller rat CNS. However, against this hypothesis is the © 2004 Adis Data Information BV. All rights reserved.
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relative specificity of fiber outgrowth to normal target sites.[35] Furthermore, the migration of xenotransplanted neurons may also be greater than equivalent allografted tissue, as has been observed using human-into-rat xenografted neurons compared with ratallografted rat neurons.[45] While there are major problems that need addressing with pig neural tissue, this has not prevented clinical use of this tissue from being undertaken. Clinical trials of porcine neural xenotransplants for both PD and Huntington disease (HD) have been initiated, with phase I data demonstrating tolerability with no evidence of PERV transmission and no significant adverse events.[46] Phase II studies in PD, using a randomized, double-blind, placebo-controlled format and follow up at 18 months post-transplantation, showed no evidence of benefit from the transplanted tissue compared with control – both groups having a 20% improvement in UPDRS.[47] However, such negative results are not surprising given the current state of knowledge of these cells in laboratory-based models of PD. 2.2.2 Stem Cells: the Ultimate Cell Source for Transplantation?
Stems cells possess the dual potential at the time of their division to produce either identical daughter cells, or cells that can specifically differentiate into more than one mature cell type that is different from the original stem cell (figure 2). Although these criteria seem prosaic, proving that a particular cell obeys both these criteria can be difficult. In fact, recent claims about the transdifferentiation potential of some stem cells has been tempered by reports that this may actually be due to cell fusion. Nevertheless, given the characteristics of stem cells, it is not hard to see why these cells, if harnessed in the correct manner, may not only overcome the problems of tissue supply but may have the potential to treat a range of disorders. However, it must be realized that there are many different types of stem cells that need to be distinguished, as they possess rather different properties and limitations. Embryonic Stem Cells
The stem cells that are generating the most interest in scientific, ethical, and political spheres are embryonic stem (ES) cells, which have the potential to generate any cell type in the body. Research involving the use of these cells of human origin are subject to a range of legal limitations ranging from a complete ban in some countries, to restricted use in others (e.g. USA), as they are obtained through in vitro fertilization (IVF) programs. At the present time, fertility treatment programs possess the technology to produce embryos containing an inner cell mass, which develops between 4 and 6 days after fertilization, that will eventually develop into all the cell types and organs of the individBiodrugs 2004; 18 (3)
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ual. It is from this inner cell mass that the ES cells are derived (figure 3). They can be kept indefinitely in an undifferentiated expanding state in vitro, if the correct conditions are maintained. Their fate can be manipulated, but by virtue of their pluripotency they also retain the potential to develop into teratomas. To date, most work has been done on murine ES cells, although in the last 5 years human ES cells have been isolated and grown.[48] In terms of an effective cell therapy, the transplantation of murine ES cells by Bjorklund et al.[49] at low density into the striatum of 6-hydroxydopamine lesioned rats produced demonstrable survival, differentiation into dopaminergic neurons, and functional recovery. This functional recovery was correlated with in vivo PET and functional magnetic resonance imaging (fMRI) changes[49] and suggested that these cells may be of therapeutic value in PD. However, 20% of the transplanted rats developed lethal teratomas and a further 24% had no evidence of graft
survival,[50] which again highlights some of the difficulties with using this particular type of stem cell. In contrast, Kim et al.[51] employed a different approach in that they pre-differentiated the mouse ES cells before transplantation in a rat model of PD. In this case, functional graft effects and survival were seen in all cases, with no teratoma formation. However, these studies employed murine not human ES cells, and it is the latter cells which will most likely be of clinical use. Neural Stem Cells or Neural Progenitor Cells
Neural stem cells can be derived from the developing brain and are more accurately termed neural progenitors as their differential or lineage potential is restricted to the three main cell types in the CNS; namely neurons, astrocytes, and oligodendrocytes (figure 3). These cells can be grown in vitro from a host of animals (including mouse, rat, pig, and human), typically in the presence of epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2).[52-55]
1. Self renewal Symmetric division
2. Differentiation Assymetric division
Neurons
Astrocytes Oligodendrocytes
Fig. 2. Diagram of stem cell criteria. Stem cells are defined as having the capacity to undertake cell division to produce daughter cells of the same phenotype, i.e. undifferentiated stem cells, as well as the ability to produce more than one differentiated cell type. In this example a neural stem cell can divide to produce daughter cells and the three main cells in the CNS, thus demonstrating the capacity to self-replicate and terminally differentiate into other cell types. © 2004 Adis Data Information BV. All rights reserved.
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Hematological cells CNS
Bone Muscle and cartilage Neurons Liver Vasculature
Oligodendrocytes Astrocytes
6−8 days after fertilization
Cells from subventricular zone or dentate gyrus Inner cell mass Adult neural stem cells
Embryonic stem cells
Multipotential cells from non-CNS regions
Fetal neural stem cells Fetal brain
Astrocytes
Neurons Transdifferentiation?
Neurons Oligodendrocytes
Fig. 3. An overview of the different stem cell types, where they are derived from and their differential potential.
These cells, when grown in culture as free floating cell cultures, form spheres, which are immature but which can be made to differentiate into neural cells by removing the epigenetic factors and providing a suitable substrate.[54,56,57] This differentiation is influenced by the age and the site of harvesting within the fetus, as well as the length of time spent in culture. Overall, the predominant phenotypes in cells differentiating out of these cultures are astrocytes and GABAergic neurons. In order for these cells to be of use for example in PD, a more controlled differentiation is required to produce dopamine-producing cells. This has been attempted using erythropoietin and low oxygen tension, and has so far proven to be one of the most successful approaches, the other being the use of pre-differentiation strategies. In this latter respect, © 2004 Adis Data Information BV. All rights reserved.
Studer et al. has grown E12 rat mesencephalon cells in FGF-2 and then allowed them to differentiate by adding serum and removing the FGF-2.[58] These same cells, when transplanted, generate tyrosine hydroxylase positive (TH+)-rich grafts with functional improvements in a rat model of PD.[58] However, this approach does not involve passaging the cells and so questions remain as to whether they were truly representative of neural stem cells. Adult Neural Precursor Cells
The last 20 years have seen the death of the long held dogma that the mammalian CNS has no adult neural stem cells. It has now been convincingly demonstrated that two major regions of the adult mammalian brain harbor neural precursor cells (NPC). The first of these regions is in the subventricular zone along the lateral Biodrugs 2004; 18 (3)
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walls of the ventricle,[59,60] where the cells form the rostral migratory stream – a system by which cells can migrate to the olfactory bulb and replace interneurons, some of which are dopaminergic.[61-64] The second region is the dentate gyrus of the hippocampal subgranular zone.[65-68] Here the NPC have been shown to produce electrically active neurons with the capacity to integrate into local neural networks within the hippocampus, and possibly mediate some memory processes. The existence of these adult NPC has raised obvious possibilities in CNS repair. Firstly, if these cells can be harvested and grown, then it may be possible to autotransplant (transplantation from one region to another in the same individual) such cells in patients. Secondly, these cells could be utilized in situ to allow rapid proliferation and replacement of the cells that are lost as part of the neurodegenerative process – assuming they themselves are not involved in the disease process itself – as we have hypothesized.[69] Indeed, some early claims have been made of clinical success in PD using such an approach,[70] although the technique remains very much in its infancy. In addition, there is emerging evidence that other regions of the CNS contain NPC,[71] and this includes the substantia nigra,[72] which obviously raises further questions about the most appropriate restorative strategy for these cells in PD. Other Stem Cells
The existence of stem cells outside of the CNS, along with claims of transdifferentiation into neural cells, has provided further opportunities for autotransplantation and repair strategies for CNS diseases. Of these alternative non-CNS sources of cells, the bone marrow stromal cell and possibly hemopoietic stem cells have so far been suggested to be able to differentiate into neural cells,[73] although the extent to which they do this is currently debated and limited. Indeed, as with ES cells, there are concerns that the reports of transdifferentiation may actually reflect cell fusion (i.e. between the transplanted cells and differentiated host cells).[74,75] Stem Cells for PD?
If stem cells are to be used in PD using the same techniques as those employed in the two randomized, placebo-controlled studies published so far, then there is no evidence to suggest that the observed dyskinetic adverse effects would not occur. However, as our understanding of the etiology of these dyskinesias evolves, a more reliable cell source, such as stem cells, placed in an appropriate anatomical location in appropriate patients may provide benefit without levodopa-independent dyskinesias. However, before © 2004 Adis Data Information BV. All rights reserved.
large-scale, placebo-controlled studies are undertaken using stem cells in PD it is mandatory that the uncertainties currently surrounding neural transplants are resolved by more animal studies and limited clinical open-label studies addressing the specific issues outlined above. 3. Other Neurological Diseases Under Consideration for Transplantation
3.1 Neural Transplants for Huntington Disease
After PD, HD is the second most studied neurodegenerative disease with the potential to be treated using neural transplantation. Based on the original research in animal models of HD, neural transplantation has been extended to involve replacement of the striatal neurons that are specifically lost in the early stages of HD. Although this disease arises as a result of a defined genetic disorder, namely a CAG trinucleotide repeat expansion in the HD gene (the function of the product, huntingtin, is as yet unknown), the neurodegenerative process leading to the specific loss of GABAergic neurons and some glutaminergic cortical neurons remains poorly understood. Thus, a reparative strategy is still required in the treatment of HD. With genetic screening of at-risk individuals, diagnosis is possible before presentation of the disease, and some research has focused on preventive measures. For example, coenzyme Q10 (ubiquinone), which serves as the electron acceptor for complexes I and II of the mitochondrial electron transport chain and an antioxidant,[76] has been shown in animal models of HD to provide therapeutic effect in combination with remacemide (a sodium channel blocker).[77] Unfortunately, this has not turned out to be the case in HD patients. The CARE-HD study (Coenzyme Q10 and Remacemide Evaluation in Huntington Disease), a randomized, double-blind, placebo-controlled study with 347 patients with early HD, whilst showing a beneficial trend with coenzyme Q10, did not show any significant slowing of functional decline.[78] Over the last 7 years, reports on clinical trials of human fetal striatal neural transplantation for HD have emerged, with about 30 patients receiving neural transplants. The initial trial data concentrated on the safety of the procedure,[79-82] with one of these studies highlighting the surgical complication of subdural hemorrhage[27] after surgery. The most likely explanation for this adverse event in this particular trial relates to the recruitment of patients with relatively advanced HD who had marked cerebral atrophy. In the same study, a patient died 18 months after receiving bilateral striatal neural implants, from unrelated causes. HistologiBiodrugs 2004; 18 (3)
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cal analysis demonstrated the survival and appropriate phenotypic development of the graft in the host brain with no evidence of immunological rejection nor HD pathology within donor-derived structures.[83] A further trial using this same approach reported efficacy data suggesting a motor and cognitive improvement in three of their five patients at 2 years after implantation, with evidence on PET scans of metabolic activity in the area of the transplant.[84] Thus, in at least one study, evidence that this approach does have benefits for HD patients[84] has been shown with graft survival, and appropriate differentiation of the transplant has been reported in another study.[83] Whilst still at an early stage of development, clinical trials in HD have also raised questions about patient selection, site of implantation and cell supply.[84] Again, problems with using human fetal tissue exist and thus alternatives have been sought. Stem cells and cells from a non-human cell source (i.e., neural xenografted cells) are emerging as the most likely cell sources to fulfill the criteria of being the ideal cell source for both HD and PD. 3.2 Amyotrophic Lateral Sclerosis
The loss of motor neurons in the ventral horn of the spinal cord and brain stem and their cortical upper motor neuron input leads to a rapidly progressive neurological disease known as amyotrophic lateral sclerosis or motor neuron disease, with death resulting less than 5 years from onset. Limb weakness and wasting with speech and swallowing difficulties are the cardinal features of this disease. At the present time there is no effective disease-modifying therapy, except possibly riluzole. Thus, more definitive therapies are required, including the use of neurotrophic factors as well as neural grafts. In the latter respect, some progress has recently been made with mouse ES cells using developmentally relevant signaling factors such as homeodomain and homeobox genes,[85] to differentiate them into spinal progenitor cells, and subsequently into motor neurons. Such ES cell-derived motor neurons can populate the embryonic spinal cord, extend axons, and form synapses with target muscles.[86] Similar advances in the production of human cholinergic motor neurons have been made recently using human fetal NPC.[87] However, the pathology in amyotrophic lateral sclerosis is anatomically diffuse, and so the original neural transplantation model of directly replacing cells at one or at most a few sites surgically is not of use clinically in this disease. Nevertheless, stem cells, given their migration and differentiation potential, may © 2004 Adis Data Information BV. All rights reserved.
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be able to do this given the correct environmental cues in terms of trophic and tropic factors. Thus, intravenous infusions of stem cells with directed migratory potential may allow a disease with widespread neuronal loss to be treated without multiple local stereotactic CNS implantations. 3.3 Multiple Sclerosis
Multiple sclerosis (MS) is a common and debilitating neurological disorder that arises as a result of immunologically induced damage to oligodendrocytes with secondary axonal and neuronal loss, and occurs at various sites throughout the CNS. Experimental transplantation of oligodendrocytes at the site of demyelination has been undertaken with limited success,[88-90] but again there are problems in generating sufficiently large numbers of these myelinforming cells as a result of the poor expansion capacity of these cells in vitro.[91,92] Furthermore, the lack of migration capacity of oligodendrocyte precursors after transplantation is poor,[91-93] and thus remote areas of demyelination will not receive the benefit from transplanted cells. In addition, there is no guarantee that such transplanted cells will not be subject to the same immunological attack that characterizes MS. However, early but extremely promising work using syngenic adult neural stem cells has addressed these two limiting aspects. Pluchino et al.[94] established neurosphere cultures from the adult CNS of mice and then injected them either intravenously or intracerebroventricularly into mice with experimental allergic encephalomyelitis – a mouse model of MS. Significant numbers of donor cells were found to have migrated into areas of active demyelination, and differentiated into appropriate cells with donor-derived remyelination occurring. The damaging gliosis that usually accompanies a demyelinating plaque was also limited, as was axonal loss, and significant functional improvement was demonstrated clinically and neurophysiologically. The remarkable migration of the neural stem cells through the blood-brain barrier to the areas of demyelination may be associated with the expression of CD44 and very late antigen (VLA)-4 by most of the neural stem cells. This would allow direct interaction with the blood brain barrier at sites of inflammation, where receptors for these surface molecules are expressed, and hence migration to sites of pathology. Translating these findings into patients is a long way off but the potential for neural stem cells to promote multifocal remyelination and functional recovery after intravenous injection can not be underestimated. The advantages of the endovascular route include the potential for widespread distribution, the ability to deliver Biodrugs 2004; 18 (3)
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Table I. Other neurological diseases to have been considered as potential candidates for neural transplantation and what would be expected of the cells to be used in each condition Disease
Cell types required
References
Alzheimer disease
Various cell types
95-97
Multiple system atrophy
Nigrostriatal and striatal cells
98,99
Traumatic spinal or brain injury
Various neural cells (site dependent)
100-106
Hippocampal damage
Hippocampal neurons
107-111
Stroke
Various neural cells (site dependent)
112-121
Brain ischemia
Vascular replacement
122,123
Epilepsy
Delivery of GABA or noradrenaline
124-129
Chronic pain
Delivery of analgesic compounds such as GABA/galanin/metenkephalins/endorphins
104,130-134
CNS malignancy
Delivery of anti-mitotic agents
135-138
Genetic defects
Delivery of metabolic enzymes
Tay-Sachs disease
β-Glucuronidase
139,140
Mucopolysaccharidosis
β-Hexoseaminidase A
139,141
large volumes, limited perturbation of neural tissue, and the feasibility of easily repeated administration.
Thus, while neural transplantation has a future, it is not clear at the present time what form this will take – in terms of which diseases, at what stage of disease and with what cells.
3.4 Miscellaneous Other Diseases
Given the diversity of cells which could be produced using stem cell technology, cells from non-human sources or engineered cell lines, and their additional properties such as their migrational abilities, numerous other neurological diseases are being considered as candidate diseases amenable to neural transplantation (see table I). 4. Conclusions The demonstration of survival, dopamine production, and functional improvement in the animal models of PD that had received fetal neural allografts of the developing ventral mesencephalon led to remarkable results in open-labeled clinical studies using a similar approach in human PD. However, when subject to randomized, double-blind, placebo-controlled clinical trials this approach proved less successful, for a variety of reasons not least of which were patient selection and the number of dopaminergic neurons surviving transplantation. This has led to a re-evaluation of neural fetal allografts as a therapy in PD. As a result, there has been a search for alternative source cells, including stem cells. These cells not only represent a potentially reliable and easily accessible supply of tissue for transplantation, but because of their inherent properties they could be used for a whole range of neural disorders, assuming their differentiation and proliferative potential can be controlled. © 2004 Adis Data Information BV. All rights reserved.
Acknowledgements Dr Harrower was a Wellcome Clinical Training Fellow and was additionally supported by the Sackler Foundation, the D R Macintosh trust, and received a Brain Scholarship from the Guarantors of Brain. The Parkinson’s Disease Society (PDS) and the Medical Research Council of the United Kingdom supported some of our work cited in this review.
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© 2004 Adis Data Information BV. All rights reserved.
Correspondence and offprints: Dr Timothy P. Harrower, Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB22PY, UK. E-mail:
[email protected]
Biodrugs 2004; 18 (3)