Stem cells offer tremendous promise for the future of transplantation. We propose examining embryonic stem cells (ESC) in monkey allografts. We will compare dopaminergic enriched ESC to fetal mesencephalic (FM) neurons in their ability to survive, innervate, and restore lost function in the best animal model of PD, the MPTP treated monkey. The primate is essential for this study to test the hypothesis that replacement strategy must completely reinnervate the very large volume of the monkey striatum. Recently clinical trials have indicated that dopaminergic (DAergic) replacement with FM neurons can cause severe debilitating dyskinesia. It is then imperative to have a clear understanding of how a DAergic enriched ESC replacement strategy affects I-dopa-induced dyskinesia (LID). In this regard, we will also compare the effects of FM transplants and DAergic enriched ESC upon the dyskinesia profile of MPTP monkeys. The potential to induce or diminish dyskinesia will be tested with the best model of dyskinesia (primate LID model). The key problem of parkinsonian transplantation with fetal or stem cells grafts is the incomplete reinnervation of host striatum. Like the FM transplant patients, focal areas of relative hyperdopaminergic activity should render these monkeys highly susceptible to LIDs. Thus to optimize reinnervation and functional recovery while minimizing the potential for dyskinesia, we will also treat DAergic enriched ESC with glial cell line-derived neurotrophic factor (GDNF) delivered via a lentiviral vector. The lenti-viral vector is critical to this hypothesis because of the proven ability to transfect the entire striatum and act not as a point source but as a volume source to stimulate reinnervation. Intraparenchymal GDNF released diffusely throughout the entire striatum should act as a developmental cue for these immature cells to extend DAergic processes throughout the striatum as well as provide neuronal rescue for dopaminergic neurons in the pars compacta of the substantia nigra. Sufficient subjects and multiple controls are included to insure proper interpretation of the data. The present series of experiments serves to provide the essential preclinical data needed to help determine the utility of nonhuman dopaminergic enriched stem cells. ? ?
