Clinical trials have provided encouraging evidence that grafts of fetal dopamine neurons are an effective therapeutic approach toward counteracting the symptoms of Parkinson's disease. Modest therapeutic benefits are observed in grafted patients despite clinical and experimental evidence that survival of grafted cells is low and graft reinnervation is incomplete. The poor survival and limited fiber outgrowth may be a consequence of neural grafts placed ectopically into an environment where the grafted neurons do not receive the proper signals for successful growth and integration into the neural circuitry of the host brain. Gene therapy may be a viable technique to introduce factors [neurotrophic factors] into brain tissue that can potentiate the survival and functional outgrowth of neural grafts, and thus improve the therapeutic value of the graft. In the proposed studies, regulated viral vectors will be injected into the lesioned nigrostriatal pathway of rodents with experimental Parkinson's disease in order to induce transgene expression of several neurotrophic factors that have a history of providing potent neurotrophic support for dopamine neurons. Subsequently, neural grafts will be implanted into lesioned/transduced brain sites and the survival, reinnervation, and function of the grafts will be assessed. Because Parkinson's disease has a higher incidence in the elderly than in the younger population, and recent experimental evidence suggests that the expression of endogenous neurotrophic factors are diminished in the aged striatum following a neurodegenerative lesion, experiments will be performed in young, middle-age, or old rats with experimental Parkinson's disease and the results will be compared within and between each age group. The studies are designed to determine the optimal temporal expression of neurotrophic factors [GDNF, BDNF, FGF-2] that improve graft development and function using regulated viral neurotrophic factors [GDNF, BDNF, FGF-2] that improve graft development and function using regulated viral vectors in young and aged animals with experimental Parkinsonism. These studies will also determine if combinations of viral vectors expressing different neurotrophic factors can be used to improve the therapeutic effects of dopamine grafts.
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| Zhang, Lixin; Fletcher-Turner, Anita; Marchionni, Mark A et al. (2004) Neurotrophic and neuroprotective effects of the neuregulin glial growth factor-2 on dopaminergic neurons in rat primary midbrain cultures. J Neurochem 91:1358-68 |
| Yurek, David M; Fletcher-Turner, Anita (2004) Comparison of embryonic stem cell-derived dopamine neuron grafts and fetal ventral mesencephalic tissue grafts: morphology and function. Cell Transplant 13:295-306 |
