The strategy of augmenting striatal dopamine (DA) levels via grafts of DA-producing cells holds great promise for the treatment of Parkinson's disease (PD). Critical to clinical success is the development of methods whereby grafted DA neuron viability and reinnervation of the host striatum are markedly increased. This objective holds true for both primary mesencephalic tissue grafts as well as for alternative tissue sources such as stem- and progenitor-derived DA neurons. The survival rate of DA neurons in fetal mesencephalic grafts to young adult rats is 5-10%. Our laboratory has recently demonstrated that this survival is even poorer in grafts to the aged striatum. Our research indicates that massive apoptotic cell death occurs within the graft during the first few days after transplantation and then sharply diminishes. Not surprisingly, this timecourse closely parallels the delay in host vascularization of the grafted cells. The lack of blood-borne nutrients, including oxygen, experienced by the grafted cells during the immediate post-grafting interval is a likely candidate to trigger apoptosis. The overall hypothesis of this proposal is that grafted DA neuron survival is severely limited by lack of blood-borne nutrients during the early post-transplantation interval when grafted cells are not adequately vascularized. Therefore augmentation of graft vascularization via gene transfer of vascular endothelial growth factor (VEGF) will significantly augment graft viability and subsequent reinnervation of the host striaturn. This strategy will be evaluated using primary mesencephalic tissue. However, results from these studies will be applicable to alternative sources of DA neurons, including stem- and progenitor-derived cells.
