DYSKINESIAS IN LENTI-GDNF TREATED PARKINSONIAN MONKEYS

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Fetal nigral grafts can cause "runaway" dyskinesias in patients with Parkinson's disease (PD;Freed et al., 2001). These dyskinesias are severe, debilitating and strongly indicate that 1) novel dopaminergic surgical therapeutic strategy planned for clinical trials need to be tested preclinically for their effects upon dyskinesias and 2) the mechanisms underlying these dyskinesias need to be elucidated. We have recently demonstrated that lentiviral gene delivery of glial cell-derived neurotrophic factor (GDNF) potently prevents motor dysfunction and prevents nigrostriatal degeneration in nonhuman primate models of PD (Kordower et al., 2000). Prior to initiating clinical trials with lenti-GDNF, it effects upon dyskinesias need to be evaluated in parkinsonian monkeys. Freed, Fahn and coworkers (2001) have hypothesized that grafted-mediated dyskinesias result from graft overgrowth. However, their own PET and post-mortem data, as well as the data from others (Kordower et al., 1995, Lee et al 1999), do not support this view. We propose an alternative hypothesis that these dyskinesias result from local "hot spots" of hyperdopaminergic function interacting with the levodopa primed brain. We plan to test this hypothesis by comparing gene therapies that induce either a) widespread or b) local hyperdopaminergic function upon dopa-induced dyskinesias and the role of dopa priming. This application will have three Specific Aims. Specific Aim 1 will test the hypothesis that lenti-GDNF treatment to non-levodopa primed MPTP-treated monkeys will prevent, or diminish the intensity of dyskinesias when they are later treated with levodopa. Specific Aim 2 will test the hypothesis that lenti-GDNF will diminish the dyskinesia profile in dyskinesic MPTP-treated monkeys previously primed with levodopa. Specific Aim 3 will test the hypothesis that "hot- spot" hyperdopaminergic function, but not homogenous hyperdopaminergic innervation, will enhance the dyskinesia profile of parkinsonian monkeys and that elimination of GDNF will reverse the functional and dyskinesic effects established previously by this trophic factor. The study of dyskinesias has become a compelling area of PD research. Exciting therapeutic strategies such as gene therapy need to be evaluated for their effects on dyskinesias so that they are both safe and effective. This application will determine whether potent dopaminergic gene therapies influence dyskinesias in the best animal model of PD.