Development of a self-regulated neuroprotective gene therapy for Parkinsons Disease and other synucleinopathies

α-突触核蛋白病是一种神经退行性疾病，其特征是细胞内α-突触核蛋白（α-synuclein，α- syn）聚集体，并且它们包括诸如帕金森氏病（PD）和路易体痴呆的病症 （DLB）。一个流行的观点是，疾病相关的因素，如衰老损害了神经元的能力， 有效清除导致细胞内聚集体形成的异常折叠蛋白质， 神经变性虽然增强错误折叠的α-syn的清除是PD的潜在治疗策略， 目前激活蛋白质降解的细胞机制的方法主要依赖于药理学诱导剂 或传统的基因传递干预。这些方法的一个转化障碍是缺乏控制 过量，精确的干预时间，以及与广泛和持续的 调节细胞降解途径。 为了满足这些治疗需求，我们建议为自给自足的人开发一种反应性基因疗法。 递送神经保护性治疗，靶向清除错误折叠的α-syn种类。在细胞模型中， α-syn种子聚集，我们将证明我们的基因治疗方法可以检测生物反应， 与α-syn（Aim 1）的积累相关，并通过调节蛋白质降解途径进行响应 （目标2）。我们希望这个项目的结果能够实现一种治疗方法， 根据受影响的大脑区域的需要，打开了在治疗的早期阶段进行干预的可能性 难治性神经退行性疾病如帕金森病 该项目具有变革的潜力，因为它引入了模块化平台技术， 与错误折叠蛋白质的神经毒性行为相关的其他神经靶点的翻译潜力（例如， 淀粉样蛋白-β，tau）。

α-Synucleinopathies are neurodegenerative diseases characterized by intracellular inclusions of α-synuclein (α- syn) aggregates and they include conditions such as Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). A prevailing view is that disease-associated factors such as aging compromise the ability of neurons to efficiently clear abnormally folded proteins which leads to the formation of intracellular aggregates and neurodegeneration. While enhancing the clearance of misfolded α-syn is a potential therapeutic strategy for PD, current methods to activate cellular mechanisms for protein degradation rely mostly on pharmacological inducers or conventional gene delivery interventions. A translational roadblock in these approaches is the lack of control over dosage, precise time of intervention, and undesirable effects associated with the broad and sustained modulation of cellular degradation pathways. To address these therapeutic needs, we propose to develop a responsive gene therapy for the self-sufficient delivery of a neuroprotective therapy targeting the clearance of misfolded α-syn species. In a cellular model of α-syn seeded aggregation, we will demonstrate that our gene therapy approach can detect biological responses associated with the accumulation of α-syn (Aim 1) and respond by modulating protein degradation pathways accordingly (Aim 2). We expect the outcomes of this project to enable a strategy where a therapy is produced as needed by the affected brain regions, opening the possibility to intervene at an early stage for the treatment of otherwise intractable neurodegenerative conditions such as PD. This project has the potential to be transformative as it introduces a modular platform technology with translational potential for other neurological targets linked to the neurotoxic behavior of misfolded proteins (e.g. amyloid-β, tau).