Substantia nigra grafts and Parkinson's disease: from animal experiments to human therapeutic trials

Abstract

During the decade since the first reports of functional effects of substantia nigra (SN) transplantation in animal models of Parkinson's disease, the procedure has progressed to human clinical trials. There is evidence that SN grafts can produce some alleviation of the manifestations of SN lesions in animal models, and by several measures these grafts appear to function in a manner similar to the normal SN. There do, however, appear to be limitations on the efficacy of SN allografts in rodent models, that may be related to an inability of fetal SN transplants to fully integrate into the host brain structure. No method of overcoming this limitation has yet been found. Studies of transplantation of human fetal SN to immunosuppressed rat hosts suggest that human donor tissue exerts proportionately greater effects than rat tissue, and is similarly effective when transplanted as solid tissue fragments or as dissociated cells. Only recently, a few controlled studies have obtained evidence for positive effects of SN grafts in primate models of Parkinson's disease. In the few clinical studies reported thus far, there are indications that some clinical improvements can be produced by SN grafts, although there is little or no evidence that the clinical changes found so far are larger than the changes that have been seen after adrenal medulla grafts. The possibility of a role of striatal injury in the clinical changes has not been resolved. It is noteworthy that nearly all of the studies of SN transplantation in rodents, primates, and humans have employed methodologies similar to those developed in the course of the first few reports on SN transplantation, and that the effects obtained by these methods are limited, even in rats. The possibility is raised that fundamental advances in SN transplantation techniques may be important for the development of a more efficacious clinical procedure.