Facioscapulohumeral muscular dystrophy (FSHD) is the most prevalent myopathy afflicting malesand females, children and adults. In the majority of clinical FSHD cases, muscle weakness is notnoticeable until the second or third decade of life followed by a progressive pathology impactingmany facets of everyday life, ranging from being unable to comb ones own hair or walk the dog toincluding having to change or abandon careers, loss of independence and, in ~20% of FSHDpatients, becoming wheelchair bound an/or require aid in breathing. Currently there are notreatments to slow down, stop, or reverse disease progression. Recent advances have identifiedthe aberrant expression of the DUX4 transcription factor as the primary initiator of the FSHDpathogenic cascade of events. In vitro studies have identified numerous DUX4-mediated eventsthat have adverse effects on cell viability and function and could conceivably lead to muscledisease if they were to happen in the context of an actual person. However, due to thecomplexities of FSHD and the lack of any valid animal model for FSHD, which, if any, of thesepathways actually has pathogenic relevance. We have successfully generated and validated aphenotypic FSHD-like mouse model based on DUX4 expression. This allows, for the first time, theinterrogation of downstream effects of DUX4 expression as to potential roles in pathophysiologyand validation as therapeutic targets. We will initially focus on the innate immune response. Themajor gene expression signature from FSHD muscle biopsies indicates the immune response ishighly activated in FSHD muscle. Many other muscular dystrophies have immune systemcomponents and there are many available ameliorative treatments for these muscular dystrophiesthat target the inflammatory response. Identifying the inflammatory response as a key mechanismin developing FSHD pathology would be a significant advance and open many new avenues fortherapeutic intervention. In addition, the design of the model allows us to initiate DUX4 expressionin adult animals. Therefore, we will use our FSHD-like mouse model to identify potentialbiomarkers of disease progression and compare with what has been found in humanbiospecimens. Importantly, in our mice we will be able to distinguish early, initiating events fromthose due to long-term cumulative effects and this may help determine which biomarkers correlatemore directly with DUX4 expression and are the best to follow as the field moves to clinical trials.
Facioscapulohumeral muscular dystrophy (FSHD); the most prevalent musculardystrophy that afflicts male and female children and adults; is severely debilitating andtreatments are lacking in part because we do not fully understand what pathways lead topathology. Our goal is to use our novel FSHD-like mouse models to identify underlyingpathogenic mechanisms in FSHD. Identification of the relevant pathogenic mechanismswill help to identify new therapeutic avenues and molecular targets.
| Jones, Takako; Jones, Peter L (2018) A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy. PLoS One 13:e0192657 |
