Therapeutic Strategies Targeting DUX4 in FSHD

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a common muscle dystrophy typically affecting patients within their second decade. Patients initially exhibit asymmetric facial and humeral muscle damage, followed by lower body muscle involvement. FSHD is associated with a derepression of DUX4 gene encoded by the D4Z4 macrosatellite located on the subtelomeric part of chromosome 4. DUX4 is a highly regulated transcription factor and its expression in skeletal muscle contributes to multiple cellular toxicities and pathologies ultimately leading to muscle weakness and atrophy. Since the discovery of the FSHD candidate gene DUX4, many cell and animal models have been designed for therapeutic approaches and clinical trials. Today there is no treatment available for FSHD patients and therapeutic strategies targeting DUX4 toxicity in skeletal muscle are being actively investigated. In this review, we will discuss different research areas that are currently being considered to alter DUX4 expression and toxicity in muscle tissue and the cell and animal models designed to date.

Keywords: DUX4; FSHD; animal models; facioscapulohumeral dystrophy; muscle; therapy.

Figure 1

Graphical summary of therapeutic strategies targeting DUX4 in facioscapulohumeral muscular dystrophy (FSHD). Diagram summarizing the different therapeutic strategies discussed in this review. Targeting DUX4-mediated toxicity in skeletal muscle was achieved by (1) genetically or epigenetically regulating DUX4 expression, (2) directly targeting DUX4 transcript by RNAi or AOs-based approaches, and (3) inhibiting DUX4 activity. Numerous studies have tried to identify proteins and signaling pathways involved in regulating DUX4 expression (top section of the diagram). These factors had either positive or negative effects on gene expression. The green star represents DUX4-repressors while the red star corresponds to enhancers of DUX4 expression. The characteristic chromatin relaxation is illustrated in light purple and the D4Z4 hypomethylation status is depicted by the light grey triangles.