Department of Neurology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 673, Rochester, NY, 14642, USA.
Neurotherapeutics. 2018 Oct;15(4):863-871. doi: 10.1007/s13311-018-00675-3.
A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of DUX4, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. DUX4 derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in SMCHD1, a gene involved in chromatin methylation (FSHD2). The resulting expression of DUX4, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting DUX4 expression or blocking 1 or more of several downstream effects of DUX4. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed.
可靠的疾病发病机制模型是开发靶向治疗的第一步。在面肩肱型肌营养不良症（FSHD）中，这是第三常见的肌肉疾病，最近在理解复杂的遗传学和表观遗传学方面的进展导致了疾病机制的确定，使该领域朝着靶向治疗的发展迈进。FSHD是由位于染色体 4q35 上的 D4Z4 大片段重复阵列上的 DUX4 反基因表达引起的，该基因在生殖细胞中表达，但通常在体细胞中被抑制。DUX4 的去抑制是由于染色质结构的开放引起的，要么是通过重复数的收缩（FSHD1），要么是由于涉及染色质甲基化的 SMCHD1 基因突变导致 D4Z4 重复的染色质低甲基化（FSHD2）。由此产生的转录调节因子 DUX4 及其靶基因的表达对骨骼肌有毒。目前针对靶向治疗的努力主要集中在干扰 DUX4 的表达或阻断 DUX4 的几个下游效应之一。这篇综述文章重点介绍了 FSHD 的潜在遗传学、发病机制的当前理解以及 FSHD 的潜在治疗策略。此外，还回顾了作为未来临床试验成功关键的新临床终点测量和生物标志物的最新进展。
