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.
Facioscapulohumeral muscular dystrophy (FSHD) is among the most common forms of muscular dystrophy. FSHD is caused when a toxic gene called DUX4 is turned ?on? in muscle. We believe that therapies for FSHD should focus on eliminating DUX4. We have developed a strategy to accomplish this using gene therapy. In this study, we will test the ability of this approach to treat muscular dystrophy in mice, and also determine the safe range of its use to prevent toxicity. We believe this study will provide a potential treatment for FSHD targeting the DUX4 gene.
