A vaccine approach to Parkinson's disease

描述（由申请人提供） 最近的工作评估基因缺陷导致帕金森病（PD） 这表明α-突触核蛋白的积累可能是一个关键步骤， 导致路易体帕金森症的致病机制。我们中的一个（RM） 开发了一种α-突触核蛋白过度表达的大鼠模型， 突触核蛋白产生的长期增加和伴随的变性 黑质酪氨酸羟化酶神经元。因为模型使用 颅内基因转移与病毒载体，它具有相当大的通用性 与转基因模型相比，其中过表达在整个过程中是恒定的， 寿命疫苗，虽然传统上被视为预防方法， 越来越多地被视为癌症的治疗药物， 心血管疾病我们中的其他人（DM和KU）发现， 淀粉样蛋白过表达的转基因小鼠模型与所有肽， 令人惊讶地有效减少阿尔茨海默氏症表型， 以及行为上的变化。本申请 将使用新的α-突触核蛋白过度表达的大鼠模型来测试 针对α-突触核蛋白的疫苗接种可以减少毒性的假设 这种药物对多巴胺产生神经元的作用。我们将使用免疫接种， 全重组蛋白和合成肽及DNA免疫 疫苗。初步研究将证实这些疫苗接种方案可以 确实在大鼠中产生高抗体滴度， 导致高稳定滴度的免疫方案。接下来我们将测试 假设这些疫苗产生的抗突触核蛋白的抗体可以 阻止由α-突触核蛋白过度引起的多巴胺能神经元的神经毒性， 表情此外，我们将研究直接注射抗突触核蛋白 抗体进入大脑，绕过血脑屏障，以评估 这种方法在挽救多巴胺能神经元中的有效性。成功将 鼓励进一步开发疫苗作为PD的治疗剂。

DESCRIPTION (provided by applicant) Recent work evaluating gene defects leading to Parkinson's Disease (PD) suggests that accumulation of alpha-synuclein may be a critical step in the pathogenic mechanisms leading to Lewy body Parkinsonism. One of us (RM) has developed a rat model of alpha-synuclein over-expression which results in long term elevations of synuclein production and concomitant degeneration of tyrosine hydroxylase neurons in substantia nigra. Because the model uses intracranial gene-transfer with viral vectors, it has considerable versatility compared to transgenic models, where over-expression is constant throughout the lifespan. Vaccines, while traditionally viewed as prophylactic approaches to disease, are increasingly being viewed as therapeutic adjuncts in cancer and cardiovascular disease. Others of us (DM and KU) have found that immunization of transgenic mouse models of amyloid over-expression with the All peptide, is surprisingly effective in reducing the Alzheimer phenotype, both pathologically and behaviorally, that develops in this model of the disease. This application will use the new rat model of alpha-synuclein over expression to test the hypothesis that vaccination against alpha-synuclein could diminish the toxicity of this agent towards dopamine producing neurons. We will use immunization with whole recombinant protein and synthetic peptides and immunization with DNA vaccines. Initial studies will verify that these vaccination regimens can indeed produce high antibody titers in rats, and determine the active immunization regimen(s) that leads to high stable titers. We will next test the hypothesis that antibodies against synuclein produced by these vaccines can arrest the neurotoxicity of dopaminergic neurons caused by alpha-synuclein over expression. Additionally, we will examine direct injections of anti-synuclein antibodies into the brain, bypassing the blood-brain barrier, to evaluate the effectiveness of this approach in rescuing dopaminergic neurons. Success will encourage further development of a vaccine as a therapeutic agent in PD.