Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent skeletal muscular dystrophies. FSHD is characterized by DNA hypomethylation of D4Z4 repeat units of a macrosatellite array found at the distal end of chromosome region 4q35, which causes a myotoxic expression of DUX4, disrupting numerous signaling pathways that converge on muscle cell death. DUX4 expression is stochastic, which complicates the development of drugs to inhibit its protein expression. There is no cure for FSHD and current standard of care focuses on managing the symptoms to improve patient quality of life.
At Epic Bio, we leverage our proprietary GEMS (Gene Expression Modulation System) platform to develop a treatment for FSHD that targets the D4Z4 epigenome and to permanently suppress DUX4 expression. Our product, EPI-321, is an AAV serotype rh74 vector encoding a catalytically inactive Cas protein fused to gene-suppressing modulators, under the expression of the CK8e promoter and a guide RNA targeting D4Z4.
EPI-321 was shown to robustly suppress DUX4 expression and downstream cascade in vitro in FHSD patient derived myocytes, indicating proper binding on D4Z4 and subsequent epigenomic silencing. Next, the functionality of EPI-321 in patient-derived myocytes was determined by examining their apoptotic rate upon treatment with NucView® Caspase 3/7 dye. A significant decrease and return to normal myocytes apoptotic levels was observed. Finally, to evaluate in vivo efficacy of EPI-321, we examined the FSHD cell content 24 days following one-time intravenous administration of EPI-321 in a humanized murine model of FSHD. In this model, EPI-321 resulted in a phenotypic rescue with 55% increased survival of skeletal muscle cells.
Taken together, these data support the development of EPI-321 as a one-time gene therapy treatment for FSHD patients. We plan to file an IND by year end 2023, and anticipate initiating first-in-human trials in 2024.