Project 2: DUX4 inhibition with non-coding RNAs as a therapeutic strategy for facioscapulohumeral muscular dystrophy (FSHD)

项目摘要/摘要 常染色体显性遗传性面肩臂肌营养不良症(FSHD)是最常见的肌肉营养不良症之一 营养不良，每7,500人中就有1人受到影响，每20,000人中就有1人受到影响。FSHD被正式归类为主要形式的 肌肉营养不良是在1954年，但导致这种疾病的致病事件直到最近才开始 对准焦点。现在有几项研究支持FSHD发病模型，该模型涉及FSHD异常表达 DUX4基因，它编码一种肌毒素转录因子。DUX4的出现代表了 FSHD领域的动量转移，因为它为治疗设计提供了一个重要的目标。事实上，就像FSHD一样 目前无法治愈的、开发有效的FSHD疗法是该领域的迫切需要。我们假设 FSHD的治疗应以抑制骨骼肌中毒性DUX4的表达为中心。这样做的目的是 建议开发安全有效的前瞻性FSHD疗法，旨在通过RNAi减少有毒的DUX4 和反义外显子跳过方法在小鼠肌肉中，使用由 腺相关病毒载体(AAV)。我们制定了三个具体目标来实现这一目标。 在完成这些目标后，我们预计将产生支持新AAV翻译的临床前数据- 基于RNAi和反义疗法的FSHD，最终可以用于翻译，朝着我们的目标 临床应用。

Project Summary/Abstract Autosomal dominant Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies, affecting 1 in 7,500 to 1 in 20,000 individuals. FSHD was formally classified as a major form of muscular dystrophy in 1954, but the pathogenic events leading to the disease have only recently started coming into focus. Several studies now support an FSHD pathogenesis model involving aberrant expression of the DUX4 gene, which encodes a myotoxic transcription factor. The emergence of DUX4 represented a momentum shift in the FSHD field as it provided an important target for therapy design. Indeed, as FSHD is currently untreatable, developing effective FSHD therapies is a critical need in the field. We hypothesized that an FSHD treatment should center on inhibiting toxic DUX4 expression in skeletal muscles. The objective of this proposal is to develop safe and effective prospective FSHD therapies aimed at reducing toxic DUX4 with RNAi and antisense exon skipping approaches in mouse muscles, using therapeutic non-coding RNAs delivered by adeno-associated viral vectors (AAV). We have designed three Specific Aims to accomplish this objective. Upon completion of these Aims, we expect to produce pre-clinical data supporting the translation of new AAV- based RNAi and antisense therapies for FSHD that can be ultimately used for translation toward our goal of clinical application.