Model animals and attempts to develop therapeutic drugs for facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common subtype of muscular dystrophy. Patients with FSHD show patchy and slowly progressive muscle weakness, and 20% of the patients over the age of 50 are deprived of their independent ambulation and require the use of a wheelchair. To date, no therapeutic drugs have been established for this disease. However, investigations on FSHD have recently progressed, including fundamental studies and clinical trials of potential therapies. Dysregulation of the expression of the double homeobox 4 (DUX4) gene, encoding a transcription factor that shows skeletal muscle toxicity, is regarded as a causative factor for skeletal muscle injury in FSHD. DUX4 is located in the D4Z4 macrosatellite repeat units of the subtelomere on chromosome 4q35. Contraction of the repeat number of the D4Z4 macrosatellite region to ≤10 (FSHD type 1) and/or pathological gene mutation of several chromatin regulators (FSHD type 2) induce DUX4 expression in skeletal muscle tissues via hypomethylation and chromatin relaxation of the D4Z4 macrosatellite. Recently, some model animals have been reported that imitate the pathophysiology of FSHD, including dysregulation of D4Z4 epigenetic control, DUX4 overexpression, and overexpression of DUX4-related factors. Therapeutic investigations using these model animals have contributed to the elucidation of the pathophysiological mechanisms of FSHD and the development of candidate therapeutic drugs. This review provides an overview of pathophysiological and therapeutic investigations using these model animals, as well as clinical trials.