Brain, Vol. 122, No. 9, 1791-1792,
September 1999
© 1999 Oxford University Press
Book reviews |
CELL TRANSPLANTATION FOR NEUROLOGICAL DISORDERS.
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Department of Clinical Neurosciences, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK
The potential goals for therapeutic use of cell transplantation in neurological disorders are ambitious. The subtitle of this book is `Toward Reconstruction of the Human Nervous System'. Most attractive may be the possibility of nigral grafts in Parkinson's disease providing reinnervation and replacement of the discrete group of cells that account for this disease. Similarly, specific striatal grafts may reconstruct cortico-striato-pallidal circuits in animal models of Huntington's disease. Indirect effects of cell transplantation include the production of trophic factors to stimulate regeneration, as with adrenal grafts, and hippocampal or cortical grafts to prevent degeneration. Even less direct, but possibly more controllable forms of cell transplantation include the manufacture of trophic and other pharmacological secreting cells, in polymers or encapsulated. A final consideration in clinical cell neurotransplantation is the possible nonspecific effect of the surgical procedure itself, including negative lesion effects of surgery, positive stimulatory effects of surgery and placebo effects.
All these aspects are considered in `Cell Transplantation for Neurological Disorders'. The technology is considered in a clinical context in this multiauthor volume. The emphasis is on technology, or practical science. One challenge is to develop and adopt appropriate trial methodologies for surgical clinical experimentation, including double-blind controlled trials. A clear message from this book is that for cell neurotransplantation to succeed it is necessary to develop teams of neurologists, neurosurgeons and laboratory scientists who are able to work to long term goals, and to work in multicentre and probably international groups. A comprehensive review of fetal nigral transplantation in Parkinson's disease is given, which has been performed in humans since the late 1980s, and similar more recent work in Huntington's disease. Other forms of transplantation are still at the laboratory or animal experimental stage, but the discussion is put in the context of human disease. Potential new areas for cell transplantation therapy include cerebral ischaemia, treatment of pain and myelin disorders.
The book commences with a description of the Lund (Sweden) transplant program for Parkinson's disease. As far back as 1975, Bjorklund and others studied survival of grafted embryonic catecholaminergic neurons implanted into the brain of adult rats, and demonstrated reinnervation of the grafts and host brain. These and related studies allowed mechanisms of graft function and survival to be investigated, leading to experiments involving nonhuman primate models of parkinsonism, including those induced by MPTP and 6OHDA.
A program to transplant embryonic neural tissue into the brain of Parkinson's disease patients was developed in 1984. Issues considered at that time, and which are discussed in individual chapters of this book in the light of subsequent experience, include methods of patient selection and evaluation, implantation technology, donor tissue properties, immunological considerations, risks of disease transmission and ethical issues. The slow progress of these studies is described in detail, including details of individual patient characteristics and responses. Reports are also presented from teams based at the University of South Florida, Fla., USA, and Creteil, France.
Some of the less successful approaches, including adrenal medullary transplantation and intraventricular injection of fetal tissues, are critically discussed in a chapter on the neuropathology of dopaminergic transplantation in human patients with Parkinson's disease. Cell survival is ~5–10% of those transplanted. The authors conclude that the human findings are very similar to those in animals, encouraging the optimization of transplantation conditions in animals prior to human trials. A short description of the role of PET scanning in assessing graft function is included, giving a reassuring indication of graft function to accompany any clinical improvement.
One of the biggest and recurring challenges in applying neural cell transplantation to humans is to avoid the use of human embryonic tissue both for ethical reasons, and because of the general difficulty of obtaining tissues. There is a delicate balance to be achieved between performing extensive primate studies and progressing to human clinical trials. The brain can be an immunologically privileged site, but this is not complete, and the grafts may be rejected by the host immune system. It appears that neural xenotransplantation may be more readily achieved in a clinical setting than other forms of xenotransplantation, such as heart, islet cell, kidney or muscle. Rejection may be low grade, and interrupted by understanding the mechanisms and intervening. The use of immunosuppressive treatment when transplanting neural tissue to the brain is considered controversial. Optimal regimes are being studied. Methods include the possibility of inducing specific donor tissue tolerance; detailed descriptions of immunological mechanisms and interventions are provided.
Huntington's disease is another neurodegenerative disease with a clearly defined phenotype, and increasingly well understood molecular pathophysiology. The development of primate models of Huntington's disease is behind that of Parkinson's disease, but both xenotransplantation, e.g. rat to baboon, pig to rat, and allotransplantation, primate to primate, have been performed and have encouraged human trials. More general lessons learnt from Parkinson's disease, related to graft survival, tissue preparation, transplantation technique, immunotherapy and trial design, may be directly applied to Huntington's disease and other neurodegenerative diseases. An interesting chapter on fetal transplantation for Huntington's disease by O. V. Kopyov and others from the Good Samaritan Hospital, Los Angeles, Calif., USA, includes a detailed case report, where fetal striatal transplantation improved symptoms for 6 months at the time of writing. The authors emphasise that much further work and study is necessary to confirm benefit.
Implantation of cells secreting pain relieving neuroactive substances, e.g. opioids, neurotensin, norepinephrine and serotonin, adopts a different approach to neural cell transplantation. Local intraspinal delivery of cells secreting these substances is equated to a `drug pump'. Specifically, adrenal medullary chromaffin cells have been used, as they secrete both opioids and catecholamines. Clinical trials at University of Illinois, Chicago, Ill., USA, and Toulouse, France, have shown improvement of pain in individual patients, but placebo-controlled blinded studies are needed.
A wider discussion of polymer-encapsulated xenogeneic cells is provided. Preclinical studies have considered effects in not only Parkinson's disease, Huntington's disease, and on pain, but also in Alzheimer's disease (nerve growth factor) and amyotrophic lateral sclerosis (ciliary neurotrophic factor). The difficulties and potential complications of this technique are also discussed, including limited diffusion of neurotransmitter or growth factors from the capsule, complications of capsule rupture, possibility of tumorous growth if cells escape the capsule, and difficulty in determining the effective dose secreted by encapsulated cells. These methods of cell transplantation also lead to a consideration of genetic manipulation of cell lines, a parallel technology, or gene therapy. This has been dealt with in more depth in the recently published preceding volume in this series of Contemporary Neuroscience, `Gene Therapy for Neurological Disorders and Brain Tumours', edited by E. Antonio Chiocca and Xandra O. Breakefield.
An important final chapter by Vawter and Gervais from the Minnesota Center for Health Care Ethics discusses the ethical issues surrounding the use of electively aborted fetuses for transplantation purposes. They consider that electively aborted fetuses deserve respect and protection beyond those of other potential cadaver donors. For example, a fetus may be at risk of being valued for his tissue rather than as a potential human being. Protection of the fetus may include the prohibition of financial and nonfinancial benefits of providing fetal tissue. It must not appear that women are being offered an abortion in order to obtain fetal tissue. The women should be prohibited from designating or knowing the identity of the recipient of the tissue, as this may be considered inappropriate as a motivation to abort, or even conceive, a fetus – in contradistinction to live human organ transplantation where donation to a relative is regarded as acceptable motivation. Further issues include respect for and protection of the woman as both a live tissue donor and next-of-kin. At the time of writing the special issues of fetal transplantation were not felt by the authors to be fully reflected in USA federal and state laws, and these issues will also require careful consideration in other countries and societies. One of the goals of the research described in this book should be to obviate the need to use human fetal tissues. The accounts given offer promise that biotechnology will in time allow us to use other forms of tissue by modification or engineering of donor tissue and host response.
Myelin disorders produce their own problems, especially the presence of multiple lesions, and suggestions that surgical transplantation could be performed on multiple occasions in patients with multiple sclerosis seems one of the more challenging suggestions for practical use of clinical cell transplantation at present. Nevertheless the message from this book is that a strong basis of scientific knowledge is being amassed, together with cautious approaches to human intervention, which in time may lead to some of these techniques becoming practical for treatment of neurological diseases. It seems that the most likely outcome will be a development of strategies to prevent progress of disease, for which for example transplantation of encapsulated genetically engineered cells producing growth factors and neurotransmitters may be appropriate. Transplantation of cells may then have a role in correcting any major neurological deficits in the context of a halted or stabilized disease state.
The general presentation of the book is excellent, and it is of manageable size. The contents are accessible to the non-expert in this field. The reader should not be put off by the difficult language in the first chapter, as this is not reflected in chapters by other authors. The most recent references date to 1996/7, and this is a rapidly developing field; but the reviews are sufficiently broad and informative that this should not make the book dated. `Cell Transplantation for Neurological Disorders' provides a sound basis for understanding upcoming new research findings, especially for interpreting and applying basic laboratory research in the clinical environment.
Notes
Edited by Thomas B. Freeman and Hakan Widner.1998. Pp. 350. New Jersey: Humana Press.
Price $125. ISBN 0-896-03449-6.
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