Pre-clinical studies with Givinostat for the treatment of dysferlinopathies
The rationale behind this proposal is based on the evidence that a key pathogenic feature of dysferlinopathies is the muscle infiltration by fat. Although the origin of this pathogenic event has not been established, the detection of adipogenic progenitors – FAPs – in muscles of the mouse model of dysferinopathies (A/J mice) and patients suggests that these cells can be implicated in the pathogenesis of the disease. As FAPs are also implicated in the pathogenesis of DMD and are the main target of a pharmacological intervention with HDAC inhibitors (HDACi) that has shown a therapeutic potential in the mouse model of Duchenne muscular dystrophy and has recently been translated into a clinical trial, we postulated that HDACi can exert similar beneficial effect in dysferlinopathies. In this project we will monitor the extent of FAP recruitment to muscles of dysferlin-deficient A/J mice at different times of disease progression, the functional characterization of FACS-sorted FAPs ex vivo, and the effect of the treatment with the HDAC inhibitor Givinostat.