Inhibitors of MBNL1 - poly(CUG)binding

描述（由申请人提供）：1型肌强直性营养不良（DM1）是一种主要遗传性疾病，可导致进行性残疾和过早死亡。DM1是最常见的形式的肌肉萎缩症在大多数转诊中心在北美和欧洲。目前还没有发现可以预防或减缓DM1进展的治疗方法。DM1的遗传基础是编码蛋白激酶的基因DMPK的3'非翻译区CTG重复序列的扩增。因为扩增的重复序列在生殖细胞和体细胞中是不稳定的，并且随着时间的推移会变大，大多数DM1患者在骨骼和心肌细胞的DM1位点上有几千个CTG重复序列。这些非常大的重复序列扩增引起了一种不寻常的RNA显性疾病过程，在这种过程中，突变等位基因的转录本（包含扩增的CUG重复序列（CUGexp））在细胞核中积累，并干扰特定基因组的RNA加工，从而产生DM1症状。这种RNA功能获得的机制至少部分涉及CUGexp RNA对MBNL家族剪接因子的隔离。MBNL蛋白以高亲和力与扩增的CUGexp RNA结合，在细胞核内形成高分子量复合物（核糖核灶），导致MBNL功能丧失。最近，我们发现cugexpm -MBNL结合的寡核苷酸抑制剂在DM1转基因小鼠模型中具有有益的作用，可引起核糖核病灶的分散，恢复MBNL活性，改善表型。作为开发DM1治疗方法的第一步，我们提出了针对MLSCN化合物集合的高通量筛选，以识别抑制CUG重复RNA -MBNL蛋白结合的小分子。

DESCRIPTION (provided by applicant): Myotonic dystrophy type 1 (DM1) is a dominantly inherited disorder that causes progressive disability and premature death. DM1 is the most common form of muscular dystrophy in most referral centers in North America and Europe. No treatment that prevents or slows the progression of DM1 has been identified. The genetic basis of DM1 is an expansion of CTG repeats in the 3' untranslated region of DMPK, a gene encoding a protein kinase. Because the expanded repeat is unstable in germline and somatic cells, and tends to grow larger over time, most individuals with DM1 have several thousand CTG repeats at the DM1 locus in skeletal and cardiac muscle cells. These very large repeat expansions give rise to an unusual RNA dominant disease process in which transcripts from the mutant allele, which contain an expanded CUG repeat (CUGexp), accumulate in the nucleus and interfere with RNA processing for a specific group of genes, thus generating symptoms of DM1. The mechanism for this RNA gain-of-function involves, at least in part, the sequestration by CUGexp RNA of splicing factors in the Muscle blind-like (MBNL) family. MBNL proteins bind to expanded CUGexp RNA with high affinity, forming high molecular weight complexes in the nucleus (ribonuclear foci), and resulting in loss of MBNL function. Recently we have found that oligonucleotide inhibitors of CUGexp-MBNL binding have beneficial effects in a transgenic mouse model of DM1, causing dispersal of ribonuclear foci, restoration of MBNL activity, and improvement of the phenotype. As a first step to developing treatments for DM1, here we propose high throughput screening against the MLSCN's compound collection to identify small molecules that inhibit CUG repeat RNA -MBNL protein binding. PUBLIC HEALTH RELEVANCE: Presently there is no treatment that can prevent muscle weakness in myotonic dystrophy, or that improves the strength of muscles that have already become weak. Recent studies suggest that myotonic dystrophy is caused, at least in part, by a harmful interaction between RNA and protein. The goal of this project is to identify substances that can block this interaction, so that they can be tested and developed as treatment for myotonic dystrophy.