Discovery of Post-transcriptional utrophin upregulator small molecules for Duchenne Muscular Dystrophy therapeutics

杜氏肌营养不良症(DMD)是一种常见的、致命的遗传病，估计每3500人中就有一人受到影响 活着出生的雄性。目前，DMD尚无明确的治疗方法，这为DMD的迫切发展提供了动力 治疗。DMD是由DMD基因突变导致Dstrophin蛋白缺失引起的。 滋养蛋白(dystrophin相关蛋白/DRP)是dystrophin的常染色体同源物，有着广泛的共同点 与抗肌营养不良蛋白的序列相似性和组织模体。已有研究表明，促性腺激素上调 能在功能上替代缺失的dystrophin，改善MDX的营养不良表型 因此，DMD的动物模型被认为是一种很有前途的治疗方法。中等程度的 上调是通过转录激活剂实现的，然而，目前还不清楚是否有转录 在临床治疗中上调就足够了，因为utroin在转录水平和转录水平上都受到调节。 转录后水平。我们和其他人已经证明了转录后机制，介导 通过5‘和3’非翻译区(UTRs)，对utroin的表达有深远的影响，并提供 DMD治疗策略的潜在靶点。在这里，我们建议合作开发和筛选一个 使用高通量筛选(HTS)的基于细胞的分析来发现、开发和验证Small 通过靶向调节的这一关键阶段来增加utroin表达的分子。这些研究将 发现具有开发成DMD疗法的巨大潜力的新型小分子。

Duchenne's Muscular Dystrophy (DMD) is a common, fatal, genetic disease estimated to affect 1 in 3500 live-born males. Currently no definitive therapy exists for DMD providing an impetus for urgently developing therapies. DMD is caused by mutations in the DMD gene leading to an absence of the dystrophin protein. Utrophin (dystrophin-related protein/DRP) is the autosomal homolog of dystrophin sharing extensive sequence similarity and organizational motifs with dystrophin. It has been shown that utrophin up-regulation can functionally substitute for the missing dystrophin and ameliorate the dystrophic phenotype of the mdx animal model of DMD, hence is considered a promising therapeutic approach. Modest degrees of upregulation have been achieved using transcription activators however, it is unclear is transcriptional upregulation will suffice in the clinical therapeutic context, since utrophin is regulated at both transcriptional and post-transcriptional levels. We and others have shown that post-transcriptional mechanisms, mediated by the 5' and 3' untranslated regions (UTRs), have a profound effect on utrophin expression and offer a potential target for DMD therapeutic strategies. Here we propose a collaboration to develop and screen a cell-based assay using High Throughput Screening (HTS) to discover, develop and validate small molecules that increase utrophin expression by targeting this key phase of regulation. These studies would identify novel small molecules with great potential for development into DMD therapeutics.