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

Duchenne肌营养不良症(DMD)是一种常见的、致命的遗传病，估计每3500名活人中就有一人受到影响。 天生的男性。目前，DMD尚无确切的治疗方法，为DMD的发展提供了迫切的动力 解决这一未得到满足的需求的疗法。DMD是由DMD基因突变导致的缺失引起的 抗肌营养不良蛋白。泛素(dystrophin相关蛋白/DRP)是dystrophin的常染色体同源物 与dystrophin有广泛的序列相似性和组织结构。促性腺激素上调可以 功能替代缺失的营养不良蛋白并改善MDX动物的营养不良表型 DMD模型，为这一方法提供了生物学验证。我们和其他人已经证明了这一点 转录后机制存在，尤其是减少或抑制肌纤维中utroin的表达。 通过将miRNAs(例如miR let-7c)与utroin的3‘非翻译区(UTR)结合。在一系列激动人心的 翻译研究，我们已经证明了阻断miR let-7c介导的与3‘UTR的相互作用 利用不同化学类别的位点阻断寡核苷酸(SBO)，促性腺激素足以抑制 抑制，增加utroin的表达，挽救营养不良的表型，在体内。重要的是，我们的 该策略的概念验证(POC)是使用磷二酰吗啉获得的 基于寡核苷酸(PMO)的SBO，其序列与人utroin基因具有100%的同源性；以及 因此非常适合翻译开发。在这份回应标准21-163的BPN提案中，我们 建议开发适合作为临床试验进入临床试验的基于SBO的促性腺激素上调药 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.