Small Molecule Approaches to Targeting the DNA and RNA in Myotonic Dystrophy

项目摘要 强直性肌营养不良1型(DM1)是成人起病的最常见形式，是一种不治之症。 神经肌肉障碍。它的遗传起源是3‘-非翻译区的三联体(CTG)重复扩增 DMPK基因的非编码区。不存在延缓疾病的治疗选择 进步。强有力的证据支持扩展的RNA转录本(RCUGexp)和它的功能获得作用 被认为是导致DM1的毒剂。RCUGexp隔离重要的蛋白质，抑制它们的 正常功能。在这些蛋白质中，最主要的是肌盲样蛋白1(MBNL1)，它是 另一种拼接。它的隔离导致&gt；100前mRNAs的错误剪接和许多症状 是DM1的。这项提案的总体目标是发现新的治疗方法，并确定和 开发靶向dCTGexp以抑制其转录的药物，以及靶向rCUGexp(如果形成)以释放隔离的 蛋白。这些药物最终可能成为治疗DM1的新的先导治疗药物。运作良好的代理 在细胞培养中，将评估模型的类药物能力(例如ADME-TOX)，适当的线索将是 在复杂的动物模型中进行测试，获得表型改善(例如，心功能)和 这与基于目标的活动(相关剪接RNA的水平)相关。该提案的具体目的是fic 它们是：(1)发现和发展与dCTGexp和rCUGexp结合的小分子，(2)发展 靶向dCTGexp和rCUGexp的自组装治疗药物，(3)靶向dCTGexp的聚合物方法 和rCUGexp，以及(4)在细胞检测、果蝇和小鼠模型中有前景的药物的评价 DM1。

Project Summary Myotonic dystrophy type 1 (DM1), the most common form of adult onset muscular dystrophy, is an incurable neuromuscular disorder. Its genetic origin is a triplet (CTG) repeat expansion in the 3'-untranslated region (UTR) of the dystrophia myotonica protein kinase (DMPK) gene. No treatment options exist to delay disease progression. Strong evidence supports a gain-of-function role for the expanded RNA transcript (rCUGexp) and it is considered the toxic agent that causes DM1. The rCUGexp sequesters important proteins, inhibiting their normal function. Chief among these proteins is muscleblind-like protein 1 (MBNL1), a key regulator of alternative splicing. Its sequestration leads to the mis-splicing of >100 pre-mRNAs and many of the symptoms of DM1. The overall goal of this proposal is to discover novel therapeutic approaches and to identify and develop agents that target dCTGexp to inhibit its transcription and rCUGexp, if formed, to liberate sequestered protein. These agents may serve ultimately as new lead therapeutic agents for DM1. Agents that function well in cell culture models will be assessed for their drug-like abilities (e.g., ADME-tox) and suitable leads will be tested in sophisticated animal models scoring both phenotypic improvements (e.g., cardiac function) and correlating this with target-based activity (levels of relevant spliced RNAs). The specific aims of the proposal are: (1) Discovery and Development of Small Molecules that Bind dCTGexp and rCUGexp, (2) Development of Self-Assembling Therapeutics Targeting dCTGexp and rCUGexp, (3) Polymer Approaches to Targeting dCTGexp and rCUGexp, and (4) Evaluation of Promising Agents in Cellular Assays and Drosophila and Mouse Models of DM1.