RNA Targeted Drug Discovery and Development for Parkinson Disease

项目摘要 帕金森病（PD）是一种常见的、进行性的和致残性的疾病，无法治愈。积累 来自人类遗传学、细胞生物学和动物模型研究的证据表明α-突触核蛋白是一种关键蛋白， 因为它错误折叠并形成可以在神经元中传播的纤维，这种现象可以解释 疾病的进行性和出现其他令人不安的症状，包括痴呆症 随着时间病理性α-突触核蛋白聚集的一个强有力的驱动因素是其在大脑中的浓度， 具有SNCA基因座倍增的个体发展早发性PD和痴呆， 剂量效应因此，降低α-突触核蛋白表达是PD的合理疾病改善策略。 这种方法针对疾病的根本发病机制，并有可能减轻 下游级联的病理事件和减缓神经变性。 使用一系列创新的化学和细胞生物学方法，我们已经确定了小分子， 选择性结合SNCA 5'非翻译区调控元件的多种化学型， 翻译，并降低稳态α-突触核蛋白蛋白水平，导致细胞保护。转录组-和 蛋白质组范围的研究表明，名为Synucleozid的领先小分子比其他小分子更具选择性。 SCNA定向的siRNA。使用Synucleozid作为原型，我们已经确定了其他不同的支架， 降低α-突触核蛋白水平，并具有血脑屏障通透性的有利特性，如定义 通过Lipinksi的5规则、CNS药物的性质和CNS-MPO计算。 在这个蓝图神经疗法项目中，我们将使用高度定制的 系统药物发现和开发漏斗。在目标1（UG 3）中，我们将采取目标验证，选择性， 和体外DMPK驱动的方法，以确定最佳的支架，以推进早期药物 化学研究，以确定结构-活性和结构-性质关系。使用迭代轮， 优化，化合物将使用全面的体外和基于细胞的筛选漏斗进行评估， 准备进入UH 3阶段。我们还将完成转录组和蛋白质组范围的选择性 后续目标（UH 3）将包括机制的体内证明、治疗性研究、 指数评估和IND使能研究，所有这些都以1期临床试验告终。

Project Summary Parkinson's disease (PD) is a common, progressive and disabling condition with no cure. Accumulating evidence from human genetics, cell biology and animal model studies suggest that α-synuclein is a key protein, as it misfolds and forms fibrils that can propagate across neurons, a phenomenon that can account for the progressive nature of the disease and the emergence of additional disturbing symptoms including dementia over time. A strong driver of pathological α-synuclein aggregation is its concentration in the brain, as individuals with multiplication of the SNCA gene locus develop early onset PD and dementia with a gene dosage effect. Thus, reducing α-synuclein protein expression is a plausible disease modifying strategy for PD. This approach targets the root pathogenetic mechanism of the disease and has the potential to mitigate downstream cascades of pathologic events and slow down neurodegeneration. Using a series of innovative chemical and cell biologic approaches, we have identified small molecules with diverse chemotypes that selectively bind to a regulatory element in the SNCA 5' untranslated region, repress translation, and reduce steady state α-synuclein protein levels leading to cytoprotection. Transcriptome- and proteome-wide studies show that the lead small molecule, named Synucleozid, is more selective than an SCNA-directed siRNA. Using Synucleozid as a prototype, we have identified additional diverse scaffolds that reduce α-synuclein protein levels and have favorable properties for blood-brain barrier penetrance, as defined by Lipinksi's Rule of 5, properties of CNS drugs, and CNS-MPO calculations. In this Blueprint Neurotherapeutics project, we will optimize these compounds using a highly tailored systematic drug discovery and development funnel. In Aim 1 (UG3), we will take a target validation, selectivity, and in vitro DMPK-driven approach to identify the optimal scaffolds to advance to early stage medicinal chemistry studies to define structure-activity and structure-property relationships. Using iterative rounds of optimization, compounds will be evaluated using a comprehensive in vitro and cell-based screening funnel in preparation for entering the UH3 phase. We will also complete transcriptome- and proteome-wide selectivity studies in PD patient-derived cells, Subsequent aims (UH3) will include in vivo proof of mechanism, therapeutic index assessment, and IND-enabling studies, all culminating in a Phase 1 clinical trial.