Necessary methodological and stem cell advances for restoration of the dopaminergic system in Parkinson's disease patients

Introduction New therapeutic non-pharmacological methodology involves cell and synaptic renewal or replacement in the living brain to restore function of neuronal systems, including the dopaminergic (DA) system in Parkinson's disease. Understanding the cell biological principles for generating functional DA neurons in lieu of the diseased can provide many new avenues for better treatment of patients with PD. Recent laboratory work has focused on using stem cells as a starting point for exogenous or endogenous derivation of the optimal DA cells for repair (Fig. 24.1). Using fetal DA cell therapy in PD patients (Piccini et al., 1999, 2000; Freed et al., 2001; Isacson et al., 2001; Mendez et al., 2002a) and stem cell-derived DA neurons in animal models (Bjorklund et al., 2002; Kim et al., 2002), it has been demonstrated that functional motor deficits associated with PD can be reduced after application of this new technology. Evidence shows that the underlying disease process does not destroy the transplanted fetal DA cells, although the patient's original DA system degeneration progresses (Piccini et al., 1999, 2000). The optimal DA cell regeneration system would reconstitute a normal network capable of restoring feedback-controlled release of DA in the nigro-striatal system (Bjorklund & Isacson, 2002). The success of cell therapy for neurological diseases is limited by access to preparation and development of highly specialized dopaminergic neurons found in the A9 and A10 region of the substantia nigra (SN) in the ventral mesencephalon, as well as technical and surgical steps associated with transplantation.