Current Therapeutic Approaches in FSHD

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies. Over the last decade, a consensus was reached regarding the underlying cause of FSHD allowing-for the first time-a targeted approach to treatment. FSHD is the result of a toxic gain-of-function from de-repression of the DUX4 gene, a gene not normally expressed in skeletal muscle. With a clear therapeutic target, there is increasing interest in drug development for FSHD, an interest buoyed by the recent therapeutic successes in other neuromuscular diseases. Herein, we review the underlying disease mechanism, potential therapeutic approaches as well as the state of trial readiness in the planning and execution of future clinical trials in FSHD.

Keywords: All neuromuscular disease; facioscapulohumeral dystrophy (FSHD); muscle disease; outcome measures.

Fig. 1

DUX4 genetics. The production of DUX4 in human muscles requires the breakdown of the multiple genetic safeguards evolved to suppress its expression in somatic cells: 1) The presence of more than 10 tandem repeat units on 4q that allow for heterochromatin condensation [91]; 2) GC-rich sequence (73%) in the repeat that allow for methylation [92]; 3) a polyadenylation signal that cannot be used in somatic/muscle cells in ∼50% of the European population [93]; 4) histone modification H3K9me3 to cause a repressive chromatin state. The utilization of the 4qA polyadenylation signal seems to be specific in somatic cells and may be aided by muscle-specific enhancers [94] in the proximal end of 4q that may aid in the transcription of DUX4 and the stabilization of the mRNA. The polyadenylation signal is critical for pre-mRNA processing and allows for DUX4 pre-mRNA cleavage and extension of polyadenylation to the mRNA [95]. The pathomechanism of derepression of DUX4 as the cause of FSHD was discovered because of careful study of the genetic structure of the 4q locus and the many naturally occurring cross-over events with the 10q subtelomere and the conclusions are: 1) A single repeat containing DUX4 is required; as an individual with complete loss of 4q subtelomeric region did not have FSHD [96]; 2) The region proximal to DUX4 on 4q and absent on 10q, including the upstream region with FRG1, SLC25A4 (ANT1) and DUX4c genes, is not required because a translocation of the most distal end of 4q to 10q resulted in FSHD; 3) 10q contraction (as found in ∼10% of the normal population) does not result in FSHD [97–99]—most likely because while 10q has similarity to the permissive 4qA alleles with the presence of 6.2-kb β-satellite sequence, it lacks the polyadenylation signal—similar to the non-permissive 4qB alleles.

Fig. 2

Targeting DUX4. Possible targeted therapeutic approaches to FSHD include: 1) epigenetic silencing of the D4Z4 repeats; 2) blocking DUX4 mRNA production by inhibiting DUX4 promoter or DUX4 mRNA formation; 3) targeting one of several identified downstream pathologic pathways triggered by DUX4 expression.