DUX4 inhibition as a therapeutic strategy for FSHD

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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.