Clinical Trials in Parkinsons Disease The Prototype for Cell Transplantation

Parkinson's disease is characterized primarily by the degeneration of dopaminergic neurons projecting from the substantia nigra to the corpus striatum. Parkinsonian clinical symptoms like rigidity, tremor, and postural imbalance, accompanied by the histopa-thologic findings of nigral distrophy and Lewy bodies, are well-described and correlate with the loss of dopamine production and release in the brain. The importance of cerebral dopamine became apparent in the late 1950s, and since then our knowledge about the neuroanatomy, physiology, and especially pharmacology of this neurotranmsitter has increased immensely. Readers interested in the topic may start by consulting the chapter in the popular neuropharmacology textbook by Cooper, Bloom, and Roth. Logically, the first therapeutic approach in diseases associated with parkinsonian symptoms, for a long time equated primarily with rigidity, was based on replacing the natural neurotransmitter with precursors like levodo-pa. This has proved to be a highly effective treatment and is still the first choice in PD. Nevertheless, some of its limitations derived from extended use and coupled with the significant progress in developmental neuro-biology have led to clinical trials using human fetal tissues as potential replacements for the degenerating adult dopaminergic neurons. For more than two decades, experimental and clinical data have accumulated to suggest that this can be a beneficial strategy for PD patients (especially those with poor response to traditional medication) and that dopamine replacement can be achieved through cell transplantation.

An important issue to be considered in brain cell transplantation is the availability and suitability of tissues from abortions. Besides the obvious ethical concerns, the basic science and clinical studies are still in progress and many questions have yet to be answered. For example, in an extensive study of 5 tissue banks funded by the National Institutes of Health (NIH), out of approximately 1500 embryonic donors, only 7 were considered to be suitable for transplantation in PD patients. Of course, this is based on the older concept that only first trimester mesence-phalic tissues from multiple donors are to be used for transplantation in one patient. Fortunately, more recent studies have shown that the use of multiple donors or first trimester tissues is not an absolute requirement to generate long-term surviving human brain grafts. Furthermore, of great promise is the current work with stem cells, which are neuronal precursors and cell lines that may soon replace the use of primary human brain cells as the main donors (Fig. 1). Finally, as will be discussed in more detail later in the article, the use of neurotrophic treatments along with viral vector technology is another exciting area in this field and may become an important approach to promote brain regeneration in PD.

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