ABSTRACT
Intracerebral transplantation of various types of cells, including primary neurons from fetal central nervous system (CNS) tissues, genetically modified cells, adrenal medulla cells, sympathetic ganglia and stem cells, has over the past two decades been proposed as a novel therapeutic approach to repair the diseased or damaged brain. Clinical trials have been started, e.g. in Parkinson’s disease (PD), Huntington’s disease, stroke, and epilepsy. However, convincing experimental data must be available before any clinical trials should be undertaken, i.e. animal data demonstrating not only functional efficacy in relevant animal models, but also a defined biological mechanism for the proposed therapeutic effect. The cell replacement strategy in PD is based on such a well-defined biological mechanism, namely the recovery of function by restoration of dopamine (DA) neurotransmission in the striatum. It was demonstrated over 20 years ago that fetal mesencephalic DA-rich tissue implanted in an animal model of PD reinnervated the denervated striatum and ameliorated some functional deficits. Extensive animal studies have subsequently shown that the grafted DA neurons display many of the morphological and functional characteristics of intrinsic DA neurons: they reinnervate the denervated striatum and form synaptic contacts with host neurons, are spontaneously active and release DA, and receive afferent inputs from the host.1 The reinnervation by the grafts is accompanied by significant amelioration of several aspects of the DA deficiency syndrome, both in rodents and monkeys.1,2 Based on these animal experimental data, the first trials with transplantation of human fetal mesencephalic tissue to the striatum in patients with PD were started in 1987. From the clinical point
of view, there is definitely a need for new therapeutic approaches in this disorder. The cell replacement strategy is also particularly suitable to explore in PD because the main pathology is a rather selective degeneration of the nigrostriatal DA system, i.e. of a specific neuronal population within a restricted area of the brain. The dopaminergic deficit in PD should, therefore, be easier to correct by transplantation as compared to, for example, the more widespread loss of many different cell types in Alzheimer’s disease.
