FETAL DOPAMINE CELLS--IMPROVING GRAFT VIABILITY

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One of the foremost difficulties with the application of neural transplantation to the treatment of neurodegenerative disorders is enhancing the survival of grafted donor tissue to ensure that adequate amounts of dopamine are produced and that transplant effect are long- lasting. One prominent laboratory reported that the survival rate of grafted, human dopamine neurons is as low as 2-5% using current techniques, tested in rodents. This laboratory and others have used this conclusion as the basis for substantially increasing the amount of tissue implanted in clinical experiments. We have been able to achieve a considerably higher survival rate in primates by studying factors which might enhance it. Improved survival of grafts may be achieved from tissue obtained from a critical stage of dopamine neurogenesis. It may be noteworthy that clinical experiments have utilized a much wider range of gestational ages than would be suggested from our new data. Moreover, we have found that chronically administered levodopa in rodents results in grafts with stunted dopamine neurons and diminished behavioral improvement. Other factors related to the preparation and storage of the donor tissue or pharmacological treatments after grafting may be equally important. Although some studies performed in rat may provide useful clues, it is understood that the greater size and complexity of the monkey brain and its similarity to the human brain makes it essential to optimize the viability of grafts in monkey models. Variables to be studied include the age of the donor tissue, graft survival over time, the method of preparation of the donor tissue such as cell suspension, solid grafts, and cryopreservation, and the effects of conventional pharmacotherapies such as levodopa, deprenyl and others on graft survival. These studies will be carried out using grafts of mesencephalic tissue into monkeys over several time periods, controlling for fetal age, matched comparisons of suspended vs. small solid grafts implanted on opposite sides of the caudate nucleus of the same monkey, fresh vs. cryopreserved tissue also implanted on opposite sides of the brain. Pharmacological studies will be done first in primate cell cultures and, if positive, subsequent experiments will test these effects on grafted monkeys. This project also will examine the effectiveness of grafts of embryonic striatum to promote growth of neurites from co-grafted mesencephalic tissue as a means of achieving greater outgrowth from grafted neurons. During the current award period we also discovered that striatal grafts have a growth enhancing effect on the host brain that can result int he growth of tyrosine hydroxylase positive fibers into grafts placed into the dorsolateral striatum. We will examine this phenomenon from the perspective of early intervention designed at protecting the residual host dopaminergic neurons.