Kainic acid is an excitatory neurotoxin that has been widely used to create lesions in the striatum that closely approximate the anatomic and biochemical abnormalities seen in Huntington's disease. It has recently been report that grafts of neonatal striatal tissue transplanted into the striata of adult rats can protect against the toxic effect of kainic acid. Preliminary studies suggest that such grafts survive and continue to protect against toxin-induced damage for at least sixty days. It has been postulated that Huntington's disease might be caused by the accumulation of an endogenous neurotoxin. The possibility therefore arises that grafts of neural tissue might protect an affected individual from the debilitating effects of this disease. A series of experiments designed to explore the potential of neural grafting as a therapeutic option in Huntington's disease is proposed. The project will be organized around four central issues; 1) the nature of the protective effect of the graft, 2) the immunological response to the graft, 3) cryopreservation of neonatal neural tissue, and 4) development of a large animal model for neural grafting. First, the nature of the protective effect of the grafts will be examined using cortical-striatal co- cultures and biochemical separation techniques. It will be determined whether these grafts protect against other known neurotoxins, and whether grafts from other species have the same protective properties. Second, the immunological response to CNS graft will be delineated using histologic, physiologic and serologic criteria. The relationship of the competence of the blood brain barrier to the immunological response will be determined. Cyclosporine will be used to inhibit rejection. Third, neonatal neural tissue will be preserved by freezing fragments comparable to grafted fragments under strictly controlled conditions and storing them in liquid nitrogen. They will then be thawed and tested for viability in vitro and in vivo. Optimal conditions for freezing and storage will be derived. Last, a large animal model will be developed. Biochemical lesions will be created in the caudate nuclei of dogs in the presence or absence of a neural graft. The size of the lesion will be assessed using noninvasive radiologic scans and histologically. The data thus generated will constitute a firm basis on which to base a rational decision regarding the feasibility of transplanting neural tissue into patients with Huntington's disease.
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