Intranigral transplantation in Parkinsonian Monkeys

描述（由申请人提供）：多巴胺分泌异位胎儿腹侧中脑（FVM）组织移植物进入纹状体，提供移植物和宿主之间的突触连接，已被证明可以改善帕金森病，但有引起迟发性失能性运动障碍的风险。我们已经证明，人类视网膜色素上皮细胞（hRPEC）的多巴分泌纹状体移植物不会引起移植物与宿主之间的突触连接，可以改善帕金森病，而不会引起运动障碍。双多巴胺能移植到黑质（SN）和纹状体可能提供更好的功能恢复和基底节区神经生理恢复，降低帕金森病（PD）运动障碍的风险。我们拟比较FVM移植物与hPvPEC移植物移植到SN和纹状体的效果，并评估此类移植物对PD动物模型药物性运动障碍的影响。所有动物都将接受左旋多巴治疗，以诱导药物性运动障碍，并定期进行行为测试（BBT），以评估帕金森病和药物性运动障碍。在特定目的1 （SA1）中，一组半帕金森病（HP）大鼠将接受FVM移植到SN和纹状体，并与仅接受FVM移植到纹状体的HP大鼠和其他对照组进行比较。在SA2中，一组HP大鼠接受黑质和纹状体hRPEC移植，另一组HP大鼠接受纹状体hRPEC移植。这两组将与对照组进行比较。基底神经节神经元活动的微电极记录，BBT评分和免疫组织化学的差异将是结果测量。为了进一步描述运动障碍期间的基底节区神经生理学，并评估双重移植物对复杂运动行为和疾病进展的影响，我们建议在MPTP治疗的猴子身上测试多巴胺能双重移植物的改善质量。在SA3中，双侧帕金森猴“准备”有药物引起的运动障碍，将接受多巴胺能双移植物FVM或hRPEC，并定期进行慢性左旋多巴暴露，以评估药物引起的运动障碍的神经生理学相关性。这些研究将测试两个独立但相互关联的问题，即宿主和移植物之间的突触连通性，以及双黑质和纹状体多巴胺能移植物在调节药物诱导的运动障碍中的作用。所提出的研究将更好地描述帕金森病和药物引起的运动障碍的病理生理，并有可能使我们接近完全恢复帕金森病黑质纹状体多巴胺能通路的理想。

DESCRIPTION (provided by applicant): Dopamine secreting heterotopic fetal ventral mesencephalic (FVM) tissue grafts into the striatum that provide synaptic connectivity between the graft and the host have been shown to improve parkinsonism but at the risk of causing delayed disabling dyskinesias. We have shown that dopa secreting striatal grafts of human retinal pigment epithelial cells (hRPEC) that do not cause synaptic connectivity between the graft and the host ameliorate parkinsonism without causing dyskinesias. Dual dopaminergic grafts into the substantia nigra (SN) and the striatum may provide better recovery of function and restoration of basal ganglia neurophysiology with reduced risk for dyskinesias in Parkinson's disease (PD). We propose to compare the effects of transplanting FVM grafts versus hPvPEC grafts into the SN and the striatum and to assess the effects of such grafts on drug induced dyskinesias in animal models of PD. All animals will be treated with levodopa to induce drug induced dyskinesias and periodically tested using a behavioral battery of tests (BBT) to assess parkinsonism and drug induced dyskinesias. In specific aim 1 (SA1), one group of hemiparkinsonian (HP) rats will receive FVM transplants into the SN and into the striatum and compared to HP rats that receive FVM grafts into the striatum alone and additional control groups. In SA2, a group of HP rats will receive nigral and striatal grafts of hRPEC while another group of HP rats will receive hRPEC grafts into the striatum alone. These 2 groups will be compared to controls. Microelectrode recordings of neuronal activity from the basal ganglia, differences in BBT scores and immunohistochemistry will be outcome measures. To further delineate basal ganglia neurophysiology during dyskinesias and to assess the effects of dual grafts on complex motor behavior and disease progression, we propose to test the ameliorative qualities of dopaminergic dual transplants in the MPTP treated monkey. In SA3, bilaterally parkinsonian monkeys "primed" to have drug induced dyskinesias will receive dopaminergic dual grafts of either FVM or hRPEC and periodically challenged with chronic levodopa exposure to assess the neurophysiological correlates of drug induced dyskinesias. These studies will test 2 separate but linked questions regarding synaptic connectivity between the host and the graft and the role of dual nigral and striatal dopaminergic grafts in modulating drug induced dyskinesias. Proposed studies will better delineate the pathophysiology of PD and drug induced dyskinesias and potentially bring us close to the ideal of complete restoration of the nigrostriatal dopaminergic pathway in PD.