In vivo efficacy studies to support the development of DUX4-targeted RNAi therapy for FSHD

常染色体显性面肩肱型肌营养不良症（FSHD）是最常见的肌营养不良症之一， 营养不良，影响1/8，333至1/20，000的个体。FSHD被正式归类为一种主要形式， 1954年发现了一种肌肉萎缩症，但导致这种疾病的致病事件只是最近才开始 进入焦点。现在有几项研究支持FSHD发病机制模型，该模型涉及以下蛋白的异常表达： DUX 4基因，其编码肌毒性转录因子。DUX 4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，正如FSHD一样， 目前无法治疗，开发有效的FSHD疗法是该领域的关键需求。我们假设 FSHD治疗应该集中于抑制骨骼肌中毒性DUX 4的表达。的目的 一项提案是开发安全有效的前瞻性FSHD疗法，旨在用RNAi减少毒性DUX 4 方法在两个新的小鼠模型FSHD，使用治疗性非编码RNA交付的腺病毒， 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。后 完成这些目标，我们期望产生临床前数据，支持新AAV的翻译， 基于RNAi的FSHD治疗，最终可以用于朝着我们的临床应用目标转化。

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies, affecting 1 in 8,333 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 approaches in two novel mouse models of FSHD, 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 a new AAV- based RNAi therapy for FSHD that can be ultimately used for translation toward our goal of clinical application.