Have a Little Heart (or Not): Highly Minimized Skeletal Muscle Regulatory Cassettes with Low or No Activity in the Heart.

Adeno-associated virus-mediated gene therapies for certain muscle disorders require regulatory cassettes that provide high-level, striated muscle-specific activity. However, cardiotoxicity has emerged as a serious concern in clinical trials for Duchenne muscular dystrophy and X-linked myotubular myopathy. While this may be caused by systemic inflammatory effects of the treatment, high transgene expression in the heart may also play a role.

FSHD Therapeutic Strategies: What Will It Take to Get to Clinic?

Facioscapulohumeral muscular dystrophy (FSHD) is arguably one of the most challenging genetic diseases to understand and treat. The disease is caused by epigenetic dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, pathogenic misexpression of in skeletal muscle.

Targeted epigenetic repression by CRISPR/dSaCas9 suppresses pathogenic expression in FSHD.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete silencing of the disease locus, leading to pathogenic misexpression of in skeletal muscle. Previously, we showed that CRISPR inhibition could successfully target and repress in FSHD myocytes. However, an effective therapy will require both efficient delivery of therapeutic components to skeletal muscles and long-term repression of the disease locus.

The Good, The Bad, and The Unexpected: Roles of DUX4 in Health and Disease.

In this issue of Developmental Cell, Chew et al. (2019) show that the pioneer factor DUX4 is misexpressed in tumors, where it suppresses anti-tumor immune activity. Their findings provide a new mechanism for immune evasion in cancer and highlight the pathogenic effects of re-expressing an embryonic program in adult cells.

The Genetics and Epigenetics of Facioscapulohumeral Muscular Dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD), a progressive myopathy that afflicts individuals of all ages, provides a powerful model of the complex interplay between genetic and epigenetic mechanisms of chromatin regulation. FSHD is caused by dysregulation of a macrosatellite repeat, either by contraction of the repeat or by mutations in silencing proteins. Both cases lead to chromatin relaxation and, in the context of a permissive allele, aberrant expression of the gene in skeletal muscle.