VP.61 An AAV-shRNA DUX4-based therapy to treat facioscapulohumeral muscular dystrophy (FSHD)

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies in adult and so far there is no curative or preventive treatment. FSHD is characterized by the aberrant expression of the <i>DUX4</i> transcription factor in muscle. DUX4 is a toxic protein, which has been implicated in myofiber death, increased sensitivity in oxidative stress, defects in myogenesis, muscle atrophy etc, ultimately leading to myofiber death. Here, we designed an AAV vector carrying a ShRNA directed against <i>DUX4</i> (AAV-shDUX4) to knock down <i>DUX4</i> expression in FSHD muscle cells and in the cre-inducible <i>DUX4</i> bi-transgenic mouse model (ACTA1-MCM/FLExDUX4). In this model, DUX4 is expressed upon Cre-mediated translocation in the nucleus, which occurs after tamoxifen injection. ACTA1-MCM/FLExDUX4 mice were injected with either an AVV-shScrambled or an AAV-shDUX4. After 4 weeks, we observed that all pathological signs of the <i>DUX4</i> expression were reduced in the AAV-shDUX4 animals compared to the AAV-shScrambled animals including: a dramatic derease in the expression of the genes downstream of <i>DUX4</i>, a decrease of the number of fibers with centrally located nuclei, a reduced inflammation etc. Our data suggest that AAV-shDUX4 based therapy is promising therapeutic strategy for FSHD.