DUX4 inhibition as a therapeutic strategy for FSHD

描述（由申请人提供）：导致FSHD的致病事件最近开始成为焦点。一些研究现在支持FSHD最终是由DUX4基因的去抑制引起的，DUX4基因编码促凋亡转录因子。DUX 4作为FSHD中的致病性损伤的出现现在使得有可能开始开发针对这种目前无法治疗的疾病的靶向疗法。该提案的长期目标是通过DUX4抑制开发FSHD的治疗方法。本文的目的是使用RNAi和新型蛋白质疗法来降低DUX4的表达和活性。该提案的具体目的是证明两种治疗方法疗效的临床前体内原理验证数据。因此，本提案的具体目标是：（1）开发针对FSHD的基于DUX4靶向RNAi的基因疗法，以及（2）开发针对FSHD的显性阴性DUX4疗法。这一提议是重要的和创新的，因为它代表了靶向FSHD治疗转化策略的第一步。

DESCRIPTION (provided by applicant): The pathogenic events leading to FSHD have recently started coming into focus. Several studies now support that FSHD is ultimately caused by de-repression of the DUX4 gene, which encodes a pro-apoptotic transcription factor. The emergence of DUX4 as a pathogenic insult in FSHD now makes it possible to begin developing targeted therapies for this currently untreatable disorder. The long-term goal of this proposal is to develop a therapeutic approach for FSHD through DUX4 inhibition. The objective here is to reduce DUX4 expression and activity using RNAi and novel protein therapies. The specific aims of this proposal are expected to demonstrate pre-clinical, in vivo proof-of-principle data on the efficacy of two therapeutic approaches. As such, the specific aims of this proposal are: (1) To develop a DUX4-targeted RNAi-based gene therapy for FSHD, and (2) To develop a dominant negative DUX4 therapy for FSHD. This proposal is significant and innovative because it represents the first steps toward a translational strategy for a targeted FSHD therapy.