Development of Utrophin Site Blocking Oligos (SBOs) to Treat Duchenne Muscular Dystrophy (DMD)

杜氏肌营养不良症（DMD）是一种常见的，致命的，遗传性疾病，估计影响1/3500的生活。 天生的男性。目前，DMD没有确定的治疗方法，这为迫切开发DMD提供了动力。 治疗来解决这一未满足的需求。DMD是由DMD基因突变引起的， 抗肌萎缩蛋白的基因肌营养不良相关蛋白（dystrophin-related protein/DRP）是肌营养不良蛋白的常染色体同源物 与肌营养不良蛋白具有广泛的序列相似性和组织基序。Utrophin上调可以 并改善mdx动物的营养不良表型 DMD模型，提供了这种方法的生物学验证。我们和其他人已经表明， 存在降低或抑制肌纤维中utrophin表达的转录后机制， 通过miRNA（例如miR let-7 c）与utrophin的3'非翻译区（UTR）的结合。在一系列激动人心的 翻译研究中，我们已经证明，阻断miR let-7 c介导的与3' UTR的相互作用， utrophin，使用不同化学类别的位点阻断寡核苷酸（SBO），足以“抑制细胞增殖”。 抑制“，增加utrophin表达，并在体内挽救营养不良表型。重要的是我们的 该策略的概念验证（POC）使用磷酰二胺吗啉代化合物获得。 基于寡核苷酸（PMO）的SBO，其与人肌营养蛋白基因具有100%序列同源性，和 因此非常适合于转化开发。在响应PAR 21-163的BPN提案中，我们 我建议开发基于SBO的utrophin上调剂，适合作为一种药物进入临床试验。 DMD的新治疗策略。

Duchenne 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 the impetus for urgently developing therapies to address this unmet need. 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. Utrophin up-regulation can functionally substitute for the missing dystrophin and ameliorate the dystrophic phenotype of the mdx animal model of DMD, providing biological validation of this approach. We and others have shown that important post-transcriptional mechanisms exist that decrease or repress utrophin expression in myofibres, in particular via binding of miRNAs (e.g. miR let-7c) to the 3' untranslated region (UTR) of utrophin. In a series of exciting translational studies, we have demonstrated that blocking miR let-7c mediated interaction with the 3’ UTR of utrophin, using different chemical classes of site blocking oligonucleotides (SBOs), is sufficient to ‘repress the repression’, increase utrophin expression, and rescue the dystrophic phenotype, in vivo. Importantly, our Proof of Concept (POC) for this strategy was obtained using a phosphorodiamidate morpholino oligonucleotide (PMO)-based SBO which has 100% sequence homology to the human utrophin gene, and hence is ideally suited for translational development. In this BPN proposal responding to PAR 21-163, we propose to develop SBO-based utrophin upregulators that are appropriate for entry into clinical trials as a novel therapeutic strategy for DMD.