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（DM 1）是成人发病型肌营养不良的最常见形式，是一种无法治愈的 神经肌肉紊乱它的遗传起源是在3 '-非翻译区的一个三联体（CTG）重复扩增 (UTR)肌强直性营养不良症蛋白激酶（DMPK）基因。没有治疗方案可以延迟疾病 进展强有力的证据支持扩展RNA转录本（rCUGexp）的功能获得作用， 被认为是导致DM 1的有毒物质。rCUGexp螯合重要蛋白质，抑制其活性 正常功能。这些蛋白质中最主要的是肌盲样蛋白1（MBNL 1），它是一种关键的调节因子， 选择性剪接它的隔离导致>100个前mRNA的错误剪接和许多症状 的DM 1。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以抑制其转录和rCUGexp（如果形成）以释放螯合的药物 蛋白这些药物可能最终成为DM 1的新的主要治疗药物。功能良好的代理 在细胞培养模型中评估它们的药物样能力（例如，ADME-tox）和合适的电极导线 在复杂的动物模型中测试，心脏功能）和 将其与基于靶标的活性（相关剪接RNA的水平）相关联。提案的具体目标 （1）发现和开发结合dCTGexp和rCUGexp的小分子，（2）开发 靶向dCTGexp和rCUGexp的自组装治疗剂，（3）靶向dCTGexp的聚合物方法 和rCUGexp，以及（4）在细胞试验和果蝇和小鼠模型中评价有希望的药物。 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.