RNA Targeted Drug Discovery and Development for Parkinson Disease

帕金森病的 RNA 靶向药物发现和开发

• 批准号: 10392570
• 负责人: Matthew D Disney
• 金额: $ 85.11万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392570
• 关键词: RNA; Targeted; Drug; Discovery; Development

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.

项目摘要 帕金森氏病（PD）是一种常见，进行性和残疾状况，无法治愈。累积 人类遗传学，细胞生物学和动物模型研究的证据表明，α-突触核蛋白是关键蛋白， 因为它不折叠并形成可以在神经元中传播的原纤维，这一现象可以解释 疾病的渐进性以及包括痴呆在内的其他令人不安的症状的出现 随着时间的推移。病理α-突触核蛋白聚集的强大驱动力是其在大脑中的浓度，如 SNCA基因基因座繁殖的个体与基因发展早期发作PD和痴呆 剂量效应。因此，还原α-突触核蛋白蛋白表达是PD的合理疾病修饰策略。 这种方法针对该疾病的根部致病机制，并有可能减轻 病理事件的下游级联和降低神经变性。 使用一系列创新的化学和细胞生物学方法，我们已经确定了与 在SNCA 5'未翻译区域中选择性结合的多种化学型，复制品 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 全蛋白质组的研究表明，铅小分子（称为synuleozid）比 SCNA定向siRNA。使用Synuleozid作为原型，我们已经确定了其他潜水员脚手架 如定义 根据Lipinksi 5的规则，CNS药物的特性和CNS-MPO计算。 在这个蓝图神经疗法项目中，我们将使用高度量身定制的化合物优化这些化合物 系统的药物发现和发育渠道。在AIM 1（UG3）中，我们将采取目标验证，选择性， 并在体外DMPK驱动的方法来识别最佳脚手架以促进早期药物 化学研究以定义结构活性和结构质地关系。使用迭代弹 优化，将使用全面的体外和基于细胞的筛选漏斗评估化合物 准备进入UH3阶段的准备。我们还将完成全转录组和全蛋白质组的选择性 在PD患者衍生细胞中的研究，随后的目标（UH3）将包括体内机制证明，治疗 指数评估和辅助研究，所有这些都在1期临床试验中达到最终形式。