Fetal nigral transplantation as a therapy for Parkinson's disease

Parkinson's disease (PD) is the second-commonest neurodegenerative disorder, affecting an estimated 1,000,000 persons in the United States alone. Resting tremor, bradykinesia, rigidity, and gait disturbance with postural instability are the cardinal clinical features of the disease (Olanow, 1996). The pathologic hallmark of PD is degeneration of neuromelanin-containing dopaminergic neurons of the substantia nigra pars compacta (SNc) coupled with intracytoplasmic proteinaceous inclusions or Lewy bodies, resulting in a reduction in striatal dopamine. Degeneration in PD can also be found in the dorsal motor nucleus of the vagus, the nucleus basalis of Meynert, the locus coeruleus, and peripheral autonomic neurons (Forno, 1996; Braak et al., 2003). Current treatment is based on a dopamine replacement strategy, primarily using the dopamine precursor levodopa (Olanow et al., 2001). In the early stages of the illness levodopa treatment is very effective, but long-term therapy is complicated by the development of motor complications (fluctuations in motor response and dyskinesias) in the majority of patients (Fahn 1992, 2000). In addition, disease progression is associated with the emergence of features that do not respond to dopaminergic therapy (e.g., postural instability, freezing of gait, autonomic dysfunction, and dementia) that are likely related to degeneration of non-dopaminergic neurons (Olanow et al., 2001). These problems limit the utility of levodopa and can represent a source of profound disability to PD patients despite the best of modern therapies. The introduction of surgical therapies, such as deep brain stimulation, represents a major advance, but these treatments are associated with their own potential adverse effects, including those related to the surgical procedure, the implantation system, and stimulation itself (The DeepBrain stimulation for PD Study Group, 2001). No therapy has yet been established to have a neuroprotective effect in PD or to restore function to disabled PD patients. There is thus a present and critical need for a therapy that slows disease progression and/or restores neurological function. Transplantation of dopaminergic neurons is a rational consideration as a novel therapy for PD because: (i) degeneration of the nigrostriatal dopaminergic system is responsible for the major motor features of PD; (ii) dopamine replacement provides dramatic clinical benefits to virtually all PD patients; (iii) dopamine neurons fire tonically and provide relatively constant synaptic dopamine levels; (iv) non-physiologic pulsatile replacement of dopamine (with levodopa) is associated with the development of motor complications; and (v) transplantation of dopaminergic neurons offers the potential of restoring dopamine in a more physiologic manner and thereby providing anti-parkinson benefits without motor complications (Olanow et al., 1996). In the laboratory, implanted fetal dopaminergic neurons have been shown to be able to survive, reinnervate the dennervated striatum, and ameliorate parkinsonian features in rodent and non-human primate models of PD (Bj?rklund and Steveni, 1979; Perlow et al., 1979; Björklund et al., 1981; Brundin and Björklund, 1987; Sladek et al., 1986; Redmond et al., 1986; Bakay et al., 1987; Bankiewicz et al., 1990). Transplanted fetal nigral allografts exhibit normal electrical firing patterns (Wuerthele, 1981), demonstrate spontaneous synthesis and release of dopamine (Schmidt et al., 1982), and form normal appearing synaptic connections with host neurons (Mahalik et al., 1985). Benefits in animal models of PD depend on the site of implantation, the type of tissue employed, and the continued presence of implanted cells, (Brundin et al., 1988; Dunnett et al., 1988). Thus, neither intrastriatal grafts of non-dopaminergic tissue nor dopaminergic grafts implanted into non-dopaminergic regions such as the cerebellum provide motor benefits in these models, illustrating the neurochemical and structural specificity of transplantation. While most transplant research aimed at treating PD has focused on human fetal nigral dopamine neurons, a number of alternate sources of dopamine producing cells have been studied. These include adrenal medullary cells, sympathetic ganglia, carotid body glomus cells, PC-12 cells, neuroblastoma cells, porcine fetal nigral cells, retinal pigmented epithelial cells, and more recently dopamine neurons derived from stem cells. This chapter will review the current status of transplantation in PD with emphasis on the recent NIH-funded prospective, double-blind clinical trials of fetal nigral transplantation and prospects for the future.