P.143 Investigation of human bone marrow mesenchymal stem cell-derived extracellular vesicles as therapeutic agents for Facioscapulohumeral muscular dystrophy

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies worldwide estimated to affect around 870,000 individuals. Both genetic and epigenetic factors can lead to FSHD, but the underlying mechanism for all types is caused by aberrant expression of the myotoxic transcription factor <i>DUX4</i>. The <i>DUX4</i> transcription factor triggers aberrant gene expression in FSHD skeletal muscle, leading to muscle differentiation defects, oxidative stress, and chronic inflammation. So far, there are no approved therapies or cure for FSHD. Our work explores the therapeutic potential of Mesenchymal stem cell-derived extracellular vesicles (MSC EVs) in FSHD and addresses an unmet need in the field. MSC EVs are known for their regenerative, antioxidant and anti-inflammatory properties. We therefore hypothesized that MSC EVs might help address these defects associated with <i>DUX4</i> expression in FSHD muscle. Accordingly, we tested the regenerative properties of human bone marrow MSC EVs using our previously published AAV.<i>DUX4</i> mouse model. When co-injected with AAV.<i>DUX4</i> in the tibialis anterior (TA) of C57BL/6 mice for two weeks, which is an acute model of DUX4-induced muscle damage, MSC EVs efficiently reduced <i>DUX4</i>-induced muscle toxicity. Surprisingly, DUX4 expression and the <i>DUX4</i>-responsive mouse biomarkers, Wfdc3 and Trim36 were decreased. In ongoing studies, we are testing the long-term impacts of MSC EVs on chronic pathology in our uninduced FSHD TIC-DUX4 mouse model and analyzing the molecular content of MSC EVs to uncover prospective mechanisms to explain the beneficial effects of MSCs on <i>DUX4</i>-associated pathology. Our preliminary results support MSC EVs as prospective therapeutic agents for FSHD.