The Ethical Issues of Trials of Neural Grafting in Patients with Neurodegenerative Conditions
Abstract and Keywords
Effective treatments of neurodegenerative disorders are increasing in importance, as the prevalence of these conditions increases with an aging population. The ethical issues around the different uses of neural tissue are essentially the same. This article focuses on the specific example of Parkinson's disease (PD) where clinical transplantation trials are most advanced. The ethical issues generated by the transplantation of the fetal material can be categorized as those relating to the patient and physician, the trial design, and tissue. The article demonstrates that the primary goal of clinical studies of fetal transplantation should be to consolidate the technical issues around patient selection, graft preparation, and surgical delivery. Each of these areas present major problems and in some ways the field, still early in development, is defining the issues as it moves forward. The solution for these issues involves a wider discussion with governmental agencies that regulate much of this work and the society that they serve and protect.
Effective treatments of neurodegenerative disorders are increasing in importance, as the prevalence of these conditions increases with an aging population. These disorders include Alzheimer’s disease, Parkinson’s disease (PD), Huntington’s disease, amyotrophic lateral sclerosis (motor neuron disease), progressive multiple sclerosis and a range of other less common conditions. In all these diseases there is progressive attrition of specific population of cells within the central nervous system (CNS) which leads to gradual, but inexorable, accumulation of disability—normally in both the physical and cognitive domains. In none of these disorders is there effective disease-modifying therapies (aggressive immunotherapy may impact on the early relapsing-remitting phase of multiple sclerosis, but has no effect on the secondary progressive phase of the disease (Compston and Coles 2008)). Consequently, there is intense research activity into innovative treatments of neurodegeneration. This includes developing more effective drug therapies (e.g. rapamycin in animal models of Huntington’s disease (Floto et al. 2007); the use of antibodies against the pathogenic protein in misfolding disorders (Holmes et al. 2008); the use of ion channel blockers to reduce metabolic stresses (e.g. lamotrigine in multiple sclerosis (Kapoor 2008)); and the delivery of growth factors (e.g. GDNF in PD (Gill et al. 2003)).
Before any of these strategies were conceived, however, was the hope that transplantation of neuronal cells could replace or repair lost cells. This approach assumes that the brain is not capable of regenerating the lost neurons itself in neurodegenerative disease. Yet that is (p. 456) not always the case. In multiple sclerosis, for instance, oligodendrocyte precursors are present in the lesions of the brain, but are not activated (Scolding et al. 1998). It is not immediately obvious cell transplantation would activate them. Tissue restoration remains a primary aim of most neural grafting programs but it is important to recognize that cell therapies could be used in other ways, such as delivering missing enzymes or neurotransmitters, locally delivering trophic and immune modulating factors to the brain, or even providing a substrate for innate axonal repair (reviewed in Barker and Dunnett 1999). In an animal model of a lethal gangliosidosis, grafts have been shown to restore function by multiple mechanisms (Lee et al. 2007).
The ethical issues around these different uses of neural tissue are essentially the same. So, in this chapter, we will focus on the specific example of PD where clinical transplantation trials are most advanced.
Neural grafting and Parkinson’s Disease
PD is a common disorder of the CNS affecting about 1 in 800 people, typically in the seventh decade of life (Foltynie et al. 2004). Classically, it is thought of as a disorder of movement secondary to the loss of the dopaminergic nigrostriatal pathway. Because of this apparent anatomical specificity, treatment with neural grafting is conceptually straightforward: dopaminergic neurons need to be implanted into the diseased nigrostriatal pathway.
Research on neural grafting for PD began around 30 years ago, most notably by BjÖrklund and colleagues in Sweden. They showed that transplantating dopaminergic tissue into the adult mammalian brain was most successful when using tissue from the fetal midbrain which contained the developing dopaminergic nigrostriatal system (6–9 weeks after conception in humans). Such tissue survives in the adult host long term, makes and receives connections with the host brain, releases dopamine, and restores many behaviors back to normal (reviewed in Wijeyekoon and Barker 2008). It was on this background that the first clinical trials were started in the late 1980s and have continued into the early part of this century.
These trials were undertaken in a number of centers within Europe (e.g. Lund, Sweden; Paris, France) as well as North America (e.g. Denver and Florida). They were small open-label studies recruiting patients with advanced disease that were failing standard drug therapies, who tended to be younger than the average patient with PD. They were assessed using a recognized international protocol called CAPIT-PD and allografted with fetal ventral mesencephalic (VM) tissue. This tissue was obtained from surgical terminations of pregnancies. Various national guidelines ensured that women were consented to the use of this tissue only after they had made a firm decision to terminate the pregnancy. The VM is that part of the developing brain which contains the neurons that will form the dopaminergic nigrostriatal pathway in the adult brain and which is lost as part of the core pathology in PD. The yield of dopaminergic cells from such a source is low, so tissue from between 4–6 fetuses was needed for grafting one side of the brain. The pooled VM tissue so collected was directly implanted into the striatum where dopamine acts. In most cases, patients also received standard immunosuppressive drugs, in protocols similar to those given to kidney transplant patients.
(p. 457) The main conclusions from these early open-label studies were that:
• The procedure itself is safe, with very few perioperative complications.
• The use of immunotherapy in patients with advanced neurological disease did not pose safety issues additional to those seen with these drugs in other settings.
• Some patients had a clear, sustained, and dramatic improvement following the transplant, both clinically and on F-Dopa positron emission tomography demonstrating the integrity of presynaptic dopaminergic terminals.
• Postmortem studies on those few patients who died after grafting, for unrelated reasons, showed the graft had survived and produced dopamine, and had extended axons into the host striatum.
The initial enthusiasm generated by these open-label trial results was dulled by reports of the success of deep brain stimulation in advanced PD (Wider et al. 2008), a technique that can more easily be set up and delivered and the negative outcomes from two double blind placebo-controlled studies investigating VM transplants in patients with PD (Freed et al. 2001; Olanow et al. 2003). These latter studies, while adopting different approaches, showed after VM transplants that:
• Patients did not significantly improve clinically compared to sham/placebo treatment.
• Some patients developed involuntary movements that did not resolve after stopping their drug therapies (so-called “graft induced dyskinesias”—GIDs).
The immediate response of the media was that a “miracle cure” had turned into a “disaster” (Boseley 2001). Uncritical acceptance of this interpretation has meant that no further trials in this area have been undertaken, although open-label studies continue to show encouraging results (Mendez et al. 2005). More sober responses have been to try to understand the apparent divergence of the trial results with previous open-label experience. For instance, one critical issue may be patient selection; PD is more heterogeneous than often appreciated, so some subtypes of the disease may be more or less responsive to transplantation (see, e.g. William-Gray et al. 2009). In addition, the pathology of PD extends outside the dopaminergic nigrostriatal pathway, involving a range of other sites within and outside the CNS which may also influence the individual response to dopaminergic transplants. Further work has suggested that GIDs may relate to the distribution of dopaminergic cells across the transplanted striatum along with contamination of the graft with co-transplanted serotoninergic neurons (Ma et al. 2002; Carlsson et al. 2007). Finally the use of immunosuppression may be more important than once thought for optimizing graft survival and efficacy.
So, there remains cautious optimism that, with more refined patient selection and graft preparation along with better trial design and immunosuppression, there may be a place for better conducted cellular transplantation trials in PD.
The ethical issues generated by the transplantation of this fetal material does though remain pressing and cannot be avoided. These can be categorized as those relating to (a) the patient and physician, (b) the trial design, and (c) the tissue.
(p. 458) The Patient and Physician
The recruitment of patients to clinical trials requires a great deal of care and is an iterative process as the optimal patient group is chosen. In early development, when safety rather than efficacy is the major issue, recruited patients tend to have more advanced disease and have failed standard therapies. As the safety profiles of therapies become more established, clinical trial recruitment is widened to include as broad a section of the patient group as sober risk/benefit assessments allow.
This tendency, to recruit patients with advanced disease, who have “least to lose,” to trials of novel therapies seems intuitively fair. However, it may compromise the trial, especially when it is difficult to sensitively measure outcome in such advanced patients. Furthermore, this approach misses the point that the potential threat of a disease is greatest before a patient has become very handicapped.
For the individual patient considering participation in a trial, the acceptable risks of an experimental treatment are balanced against the perceived threat of the disease. It is important, therefore, that the physician not only explains the trial procedures and risks, but also ensures that the patient has a reasonable perception of his or her disease and its prognosis. Several factors confound this process. Firstly, cognitive deficits in advanced PD are common (Williams-Gray et al. 2009) and interfere with the ability to fully appreciate the risks of treatment. Dysexecutive problems in PD have been well described in early disease (Foltynie et al. 2004; Williams-Gray et al. 2009); whilst it is not clear how they affect everyday activities of daily living, they may well impede the ability to assimilate complex and competing sets of information—as would be needed to consent for any cell therapy trial. Even subtle deficits may interfere with a full understanding of the risks inherent in a trial of an experimental therapy. Secondly, even in cognitively normal patients, rational thinking may be clouded by the hope, even desperation, that the treatment might give personal benefit. Sometimes these hopes have been inflamed by histrionic media reports, internet chatroom rumors, or relatives struggling to cope with the affected person. Thirdly, a particularly difficult element of the consenting process in experimental therapies is the attitude of the patient and physician to uncertainty. In fetal cell therapies for PD there may be considerable unforeseeable risks. It is worth overtly discussing a patient’s attitude to risk, much in the way an investment broker might. For someone who values safety above all else, fetal grafting may not be appropriate.
The person taking consent needs to be aware of all these dynamics, and ensure that a realistic account of the known advantages and disadvantages of the trial is understood. In our experience, the patient information sheet, which is so scrutinized by the ethics committee, cannot be relied upon. Each potential trial participant has to receive an explanation of its pros and cons in language and detail tailored for their particular situation and background. This is usually best done at several meetings. And the process of information delivery does not stop once the patient is recruited. An audit of patients in trials, of which one of us was the principal investigator, found a high level of satisfaction with the consenting process, but a surprising inability of participants to remember the aim of the trial and the chief adverse effects of the investigational drug (Cox, Association of British Neurologists, 1999). We concluded that these important points need to be regularly reiterated as the trial proceeds.
Given the highly technical and sophisticated nature of fetal grafting for PD, it is likely that it will only take place in a few centers internationally. To begin with, at least, the few (p. 459) physicians involved will naturally be advocates of the approach and may well have considerable career investment in a successful outcome. Whilst ensuring enthusiasm, this tendency allows the possibility that the physician consenting a patient either consciously, or more likely unconsciously, “sells” the trial to boost recruitment. In principle, a neutral third party would be better placed to advise and consent the patient. But, in early trials of complex treatments, it is hard to find physicians with sufficient understanding who are not already committed to the program.
In summary, various pressures bear on the physician and patient considering a trial of neural transplantation. The investigator needs to be aware of these, particularly the possibility of subtle cognitive impairment in many of the relevant diseases. He or she ultimately needs to ensure that trial participants understand, in their own terms, their disease, its prognosis, best standard therapy, and the possible benefits and harm of the grafting procedure. This understanding needs to be regularly checked and reinforced as the trial proceeds, which of course may be on a background of changing cognitive abilities in the affected trial patient.
The Ethics of Trial Design
Trial design is an ethical issue. The utilitarian approach is to define the ethical position of any clinical trial as the balance between management of the individual participant and the potential gains to the wider community. For those trial patients taking an active agent, the possible good of a successful treatment should outweigh the potential harmful effects of the drug or disease progression. To the wider community of disease sufferers, there is the potential good that an effective treatment will be discovered. In addition a well-conducted trial, irrespective of its result, should always advance understanding of the disease and so benefit a wide population. A definite negative trial result minimizes the potential harm to the wider community, whereas an inconclusive trial is a waste of resources, time, and participants’ good will. Underpowered trials fall into this category. Concerns have been raised about the power of the two NIH PD transplantation studies, with 20 and 23 initially grafted in the two trials respectively with control arms (sham surgery) of 20 and 11 respectively, and of the GDNF trials in PD (Barker 2009). One way of improving power, without exposing more patients to transplantation, is to randomize patients to immediate or delayed grafting. This allows for a comparison between grafted and non-grafted patients during the first half of the trial and before and after grafting of the delayed group, acting as their own controls. This approach has been adopted in a large transplant study in Huntington’s disease, where patients that are not grafted in the first phase of the study are transplanted 2 years later (A. Bachoud-Levi, personal communication).
Utilitarianism needs to be constrained by deontological ethics, where primacy is given neither to outcome nor utility but to motive and ethical principles. One such approach, for instance, would be the principle of non-maleficence, “first do no harm.” Superficially, a strict application of this rule would disallow all clinical trials. But, appealing to the principle of autonomy, Schafer wrote that: “human dignity can be severely undermined by serious illness as well as by the human experimentation designed to eliminate such illness. There is an ethical cost attached to not doing such research as well as to proceeding with it” (Schafer 1982). (p. 460) This is manifestly true of progressive neurological diseases such as PD and multiple sclerosis.
The relative weight of collective and individual ethics depends on the aims of the trial. In phase 1 studies, individual ethics should predominate, as the information derived from such a trial will not be applied directly to the wider community but will lead at most to a phase 2 study. This means that the iconic placebo-controlled double-blinded design of drug trials may not be most appropriate for phase 1 transplantation studies. For instance, the sham surgery of recent PD transplantation trials is clearly more risky than a placebo pill. Patients went to theatre to have a burr hole drilled through their skull but without penetrating the dura. In one of trials (Olanow et al. 2003) all patients had 6 months of immunosuppression, including those who had imitation transplant surgery. The question is not whether such controls are technically correct, as they clearly are, but whether the risks to the individual participants, which for imitation transplant surgery and 6 months of immunosuppression are appreciable, are justifiable. We believe they may not be, because the techniques for graft preparation and insertion are not yet sufficiently optimized. So the benefit to the collective is likely to be small from current trials, as different grafting regimens are explored, and the emphasis must be on reducing risk to the trial participants themselves.
Once a transplantation trial has concluded, media attention can be expected. Results may be widely and uncritically cited, and may well be given more prominence than is justified by their true clinical impact. This is particularly damaging when negative trial results are used to damn the strategy of neural grafting. A transplant may fail to help a disease, not because there is anything wrong with the cell therapy itself, but because the wrong patients have been included, or the trial design was inappropriate.
A particular problem in transplantation trials, which rarely affects drug development, is that patients can purchase cellular therapies. “Stem cells” are sold all over the world in an unregulated way. One company, for instance, took to selling stem cells in the toilets of a ferry between the UK and Ireland in order to avoid regulatory compliance (Panorama: Stem Cells and Miracles 2009)! Trading off the publicity generated by reputable centers doing transplantation trials, such unscrupulous businesses exploit desperate patients. They undermine the reputation of neural grafting and fail to provide any useful scientific data to advance the field. Very likely, the only beneficiaries are the businesses and its investors.
We believe that the development of neural grafting cannot be directly borrowed from the well-honed system for drug approval. At present, we believe the primary goal of clinical studies of fetal transplantation should be to consolidate the technical issues around patient selection, graft preparation, and surgical delivery. In this context, we do not think imitation transplant surgery or immunosuppression of ungrafted patients can easily be justified. Only when the technique is more consolidated can power calculations be reasonably made and controlled trials set up.
The grafted tissue
A number of different cell sources have been considered for use in patients with neurological disease (Laguna Goya et al. 2008). These have included:
• Fully differentiated adult tissue that can then be autografted (e.g. carotid body transplants in PD).
• Adult cells that have been simply manipulated to adopt more of a neuronal, dopaminergic phenotype (e.g. adrenal medullary transplants in PD).
• Adult cells that have been de-differentiated into more primitive neural precursor cells (e.g. induced pluripotent stem cells (iPS cells) in motor neuron disease (Ebert et al. 2009).
• Fetal cells derived from the developing brain, which involves collecting tissue from elective termination of pregnancies (e.g. fetal VM or striatal allografts in PD and Huntington’s disease respectively).
• Cells derived from the embryo at a very early stage of development, such as the blastocyst—so-called embryonic stem or embryonic stem cell cells (e.g. dopaminergic neurons for use in PD).
• Engineered cell lines derived from a range of sources (e.g. the cell lines MHP36 used in a variety of experimental CNS disease and soon to be used in clinical trials in patients with stokes).
Each of these cells brings with them their own unique advantages and disadvantages. In the early stages of development, transplantation of adult adrenal medullary tissue was used in PD. However, whilst some initial success was claimed (Madrazo et al. 1987), it soon became apparent that this tissue survived poorly, if at all, and had minimal lasting clinical benefits in patients (Goetz et al. 1989). This has been the usual outcome whenever adult post-mitotic tissue has been used as graft. The best hope for adult tissue grafting come from improved carotid body autografts or using induced pluripotent stem cells (iPS cells).
Stem cells are an exciting potential future source of cells for transplantation programs. They are defined by their capacity to divide and self-propagate whilst also retaining the capacity to differentiate into other cell types. There are many different sources of stem cells, with unique benefits and disadvantages. Three in particular could be treatments of neurodegenerative disorders. Mesenchymal stem cells derived from the adult bone marrow are now being trialed in a range of neurological disorders including stroke, multiple system atrophy, and, more recently, multiple sclerosis (Freedman et al. 2010) Their mechanism of action is complex. It has not yet been shown that they can truly transdifferentiate into mature neural elements. Nevertheless they may be able to support the degenerating CNS networks through the release of trophic and immunosuppressive factors. These cells are relatively easy to obtain but we remain to be convinced that they can truly make a clinically significant long-term impact in patients with neurological disorders (e.g. Quinn et al. 2008).
The second stem cell source for cell therapy is the embryonic stem cell. These cells are derived from blastocysts redundant to the needs of couples undergoing in vitro fertilization programs. The key ethical issue is the moral status of the inner cell mass of the blastocyst, which has not yet differentiated into any recognizable fetal elements. At what point, in the long and complex process from fertilization to delivery of baby, does humanness or personhood start? This complex question cannot be adequately addressed here. Simplistically put, there are two positions. Some take a gradualist approach, where the embryo becomes more human and more deserving of protection as it develops biologically. In effect, this is the position adopted in law in most countries. The alternative position is to identify an absolute threshold at which a non-living lump of material becomes a fully-fledged person, with all human rights. Historically, different times have been suggested for the emergence of personhood or ensoulment: at fertilization, quickening (first movements), at the time beyond (p. 462) which twinning is no longer possible, or at birth. To our knowledge, the most helpful and comprehensive survey of these various positions, and their implications, is that of David Jones (2004).
Attempts to harvest stem cells without raising these ethical concerns have been developed. Widely publicized techniques to isolate individual cells from the developing blastocyst without destroying it (Klimanskaya et al. 2006) have yet to be replicated. Alternatively, and most excitingly, has been the announcement that adult cells can be reprogrammed to a more primitive pluripotent state, which resembles an embryonic stem cell. The technology to generate these iPS cells has made much progress over the last few years. IPS cells have now been made from both adult mouse and human cells from a variety of sources but most notably skin fibroblasts. These are then back-differentiated to stem cells and driven down a new differentiation pathway, initially using oncogenes and viral vectors (Takahashi et al. 2007), but more recently by safer technologies (Soldner et al. 2009). The current situation is that, in mice, neuronal elements can be generated from adult skin cells which have some functional benefits in a model of PD (Wernig et al. 2008). Not only does this technology avoid the ethical issues of embryo harvesting, but it provides tissue that is easily available (from the patient directly), which is uninfected and will not be immunologically rejected. However, these cells are not yet ready for clinical use. Furthermore, if the cells are derived from the patient with a neurological disease themselves, it is possible that the derived tissue may be vulnerable to the original pathology. And there are concerns, as with all embryonic stem cell treatments, over the extent to which all cells can be directed to a mature neural fate. Any residual undifferentiated cells could form a tumor; the proliferative potential of differentiated human embryonic stem cell transplants in vivo has been reported (Roy et al. 2006) and there is a case report of a brain tumor arising from a neural graft used to treat ataxia telangiectasia (Amariglio et al. 2009). The moral status of iPS cells remains largely undiscussed. A key issue is whether or not such cells can generate a human person in much the same way as an embryonic stem cell. But at least their source is not ethically contentious; as tattooing and cosmetic surgery is socially acceptable, using adult human skin to treat disease seems positively lofty!
Although there are great hopes that iPS cells could be used in transplantation, that prospect remains distant. Pragmatically, there is currently only one viable option for cell transplantation in PD: fetal tissue.
The use of human fetal tissue requires the collection of material acquired through elective terminations of pregnancy. Unfortunately, fetal material from spontaneous miscarriages cannot be used for a number of reasons: (1) it is often unclear how long the material has been dead for; (2) the tissue may have acquired an in utero infection; and (3) the cause of the miscarriage, which is usually unknown, may have been a problem with the developing fetus which would preclude its use as donor tissue. For this reason, the fetal material for grafting has to be collected from elective surgical termination of pregnancy, although there is a growing interest in whether tissue from medical terminations could also be used.
In some countries, the medical use of fetal material is not permitted. This does not avoid ethical difficulties though. For example, before Bill Clinton came to power in 1992 in the US, human fetal allotransplant work in patients with neurodegenerative disorders could not be federally funded, so it became the preserve of the private sector. This decision placed greater value on the ethic of the free market. It is not at all clear that rescinding to commerce (p. 463) promotes an ethical approach to fetal transplantation. Furthermore, medical tourism means that physicians may be asked by patients to comment on trials, which would not be permitted in his or her country, but are nevertheless accessible.
Some will argue that, in countries where termination of pregnancy is legal, there are no ethical issues involved in using the “waste products.” In this line of thinking, it is better to make some good use of the material, to potentially benefit others, than let it be thrown away. This is an intuitively powerful argument and, superficially, is similar to cadaveric organ donation. One does not wish for people to die in accidents, but it will happen and it is good that their organs can be used to help others, and their use does not condone the cause of death.
However attractive this argument appears, it fails to address two key points, the first being the status of the fetus. In the cadaveric organ transplantation example, the status of the dead person is fairly universally recognized and this leads to social strictures around the treatment of the body. For instance, many would be offended by the use of a cadaver for cosmetic research. So, to define whether or not the use of fetal grafts as treatment is acceptable, it is necessary to address what the fetus is, whether person, human, animal, or none of these. As with the moral status of the blastocyst, this topic is too complex to address fully but we make some comments briefly here. Secondly, it is not possible to completely divorce the ethics of the use of the products of termination of pregnancy from the ethics of the procedure itself. To stretch the analogy: if traffic accidents were deliberately committed in order to farm organs for transplantation, the use of the material, however effective in relieving suffering, would be seen to be complicit with murder and unethical. Of course, all fetal cell transplantation programs are structured to ensure that there is no coercion of women considering termination. Nevertheless individuals involved in transplantation programs may feel involved in the source of the tissue. The relation between distance from the act of termination, and complicity in it, is finely argued by Edward Furton (2003). A more systemic issue is that if society allows fetal cell transplantation, as in the UK, this may impact on the ethical environment in which people make decisions about termination of pregnancy. It is possible that the perception that “some good will come from a bad situation” may nuance occasional decisions in favor of termination. Even if this happens very infrequently, it ties the ethics of termination with the use of fetal material.
In this chapter we have laid out the major issues with respect to the ethical problems confronting the field of neural transplantation. These issues encompass the patient themselves, the cell to be used and the trial design. Each of these areas presents major problems and in some ways the field, still early in development, is defining the issues as it moves forward. Exactly how these issues will be resolved in the future requires active debate and the involvement of those outside of the medical profession including ethicists, social scientists, and philosophers. It also will involve a wider discussion with governmental agencies that regulate much of this work and the society that they serve and protect.
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