EVALUATION OF PROSAVIN EFFICACY TO MPTP-LESIONED MACAQUES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 在中枢神经系统中使用病毒载体作为治疗药物的载体是治疗神经退行性疾病特别是帕金森病的一个非常有兴趣的领域，因为黑质纹状体多巴胺能神经元优先丢失，而且目前使用的长期多巴胺替代疗法会导致严重的副作用，大大限制了这种治疗方法在晚期患者中的使用。在本项目中，史密斯博士开发了一项由英国牛津生物医学公司支持的研究计划，以确定在MPTP治疗的帕金森氏病非人类灵长类动物模型中，导入多巴胺合成所需酶和辅助因子的慢病毒载体(在此称为ProSavin)抗帕金森病的有效性。一组7只猴子在长期注射MPTP毒素后出现帕金森氏症，然后在连合后壳核的感觉运动区域接受5次10微升(即每个结构总共50微升)的病毒载体注射。注射后，动物被允许存活3-6个月，在此期间，每周都会监测它们的行为，以评估它们帕金森症状的变化。到目前为止获得的数据表明，接受载体注射的一些猴子的行为有所改善，但并不是所有的猴子都有。尸检研究正在进行中，以评估纹状体转基因的程度和由此产生的纹状体多巴胺神经支配的程度。这些在非人类灵长类动物身上的发现将成为帕金森氏症患者临床试验的基本基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The use of viral vectors as carriers of therapeutic agents in the CNS is a field of great interest for the treatment of neurodegenerative diseases, most particularly for Parkinson's disease, because of the preferential loss of nigrostriatal dopaminergic neurons, and the fact that the currently used long term dopamine replacement therapy results in major side effects that considerably limit the use of such therapeutic approach in advanced patients. In the present project, Dr Smith has developed a research program supported by Oxford Biomedica in UK to determine the antiparkinsonian efficacy of a lentiviral vector transfected with the necessary enzymes and co-factor for dopamine synthesis (hereby called Prosavin), in the MPTP-treated nonhuman primate model of Parkinson's disease. A group of seven monkeys were rendered parkinsonian following chronic injections of the toxin MPTP before they received five injections of 10 microliters (ie a total of 50 microliters per structure) of the viral vector in the sensorimotor territory of the postcommissural putamen. Following the injections, animals were allowed to survive for a period of 3-6 months during which their behavior was monitored on a weekly basis to assess changes in their parkinsonian symptoms. Data obtained so far have indicated modest behavioral improvement in some, but not all monkeys that received the vector injections. Postmortem studies are in progress to assess the extent of striatal transfection and the resulting degree of striatal dopamine innervation. These findings in nonhuman primates will serve as the basic foundation for clinical trials in humans with Parkinson's disease.