A vaccine approach to Parkinson's disease

描述(由申请人提供) 最近评估导致帕金森氏病(PD)的基因缺陷的工作 提示α-突触核蛋白的积累可能是 路易体帕金森综合征的发病机制。我们中的一个(RM)有 建立了一种α-突触核蛋白过度表达的大鼠模型，该模型导致长时间 突触核蛋白产量的长期升高和伴随的退变 黑质内的酪氨酸羟基酶神经元。因为该模型使用 利用病毒载体进行颅内基因转移，具有相当大的通用性 与转基因模型相比，在转基因模型中，过度表达在整个 寿命。疫苗，虽然传统上被视为预防方法，但 疾病，正越来越多地被视为癌症和 心血管疾病。我们中的其他人(DM和KU)发现免疫接种 ALL多肽过度表达的转基因小鼠模型 在减少阿尔茨海默病表型方面令人惊讶地有效，从病理上讲 在这种疾病模型中发展起来的行为。此应用程序 将使用新的α-突触核蛋白过度表达的大鼠模型来测试 假设接种α-突触核蛋白疫苗可以降低毒性 这种药物对产生多巴胺的神经元的作用。我们将使用免疫接种 全重组蛋白和合成肽及其DNA免疫 疫苗。初步研究将证实这些疫苗接种方案可以 确实在老鼠身上产生了高抗体效价，并确定了活性 导致高稳定滴度的免疫方案(S)。接下来我们将测试 假设这些疫苗产生的针对突触核蛋白的抗体可以 阻断α-突触核蛋白对多巴胺能神经元的神经毒性 表情。此外，我们还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方面的有效性。成功将会 鼓励进一步开发疫苗作为帕金森病的治疗剂。

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.