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人们关注的焦点。现在有几项研究支持FSHD最终是由DUX4基因的去抑制引起的，该基因编码促凋亡转录因子。DUX4作为FSHD致病性损伤的出现，现在使得开始开发针对这种目前无法治疗的疾病的靶向治疗成为可能。该提案的长期目标是开发一种通过DUX4抑制治疗FSHD的方法。目的是利用RNAi和新型蛋白疗法降低DUX4的表达和活性。该提案的具体目的是期望证明两种治疗方法有效性的临床前，体内原理证明数据。因此，本提案的具体目标是：(1)开发一种针对DUX4的基于rnai的FSHD基因疗法，以及(2)开发一种针对FSHD的显性阴性DUX4疗法。这一建议意义重大，具有创新性，因为它代表了靶向FSHD治疗的转化策略的第一步。

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. PUBLIC HEALTH RELEVANCE: Elevated levels of the DUX4 gene have been recently linked to development of Facioscapulohumeral Muscular Dystrophy (FSHD), one of the most common diseases of muscle. We propose that inhibiting DUX4 expression and activity in muscles will improve muscular dystrophy in FSHD patients. In this proposal, we will test two DUX4 inhibition strategies using gene therapy.