P.339 - Generation of a new, inducible model of FSHD that develops overt myopathic phenotypes

Abstract

Autosomal dominant Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent muscular dystrophies, estimated to affect as many as 1 in 8,333 individuals worldwide. FSHD was 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 we are no longer solely focused on understanding FSHD pathogenesis, and can now turn an eye toward translational research. Mouse models are important tools for translational research, but there are currently no published DUX4-expressing germline models that develop myopathic phenotypes useful as outcome measures, largely due to the extreme toxicity of DUX4 making it difficult to generate such animals. The absence of valid FSHD mice is a hurdle to testing therapies, thereby making development of FSHD mouse models a critical need in the field. Our goal was to generate an FSHD mouse model that develops to adulthood, contains a heritable transgene, and shows myopathic phenotypes that can be used as outcome measures for DUX4-targeted therapies. We created a novel FSHD mouse model in which DUX4 can be expressed in skeletal muscle using Tamoxifen-inducible CRE recombinase (called iDUX4 mice). We have generated the first FSHD mouse model that expresses a heritable DUX4 transgene and displays myopathic phenotypes useful as outcome measures for therapy development, including molecular, histopathological, and functional deficits. Our iDUX4 mice display Tamoxifen and DUX4 dose-dependent molecular, histopathological, and functional deficits associated with muscular dystrophy and will be used for testing therapeutic strategies targeting DUX4.