FSHD iPS cells: Modeling disease mechanisms, genetic correction and cell therapy

描述（由申请人提供）：面肩肱骨肌营养不良症（FSHD）是一种遗传显性进行性肌病，在美国影响约25,000人。它是第三大最常见的肌肉萎缩症发病率接近或超过杜氏症。与该疾病相关的DNA损伤是在4q端粒附近的一系列3.3 kb重复序列（D4Z4重复序列）内的收缩。目前尚不清楚这种收缩是如何导致疾病的，但它似乎改变了4q35.2的染色质结构，并已提出导致附近基因的抑制。为了阐明疾病机制并加快潜在的细胞治疗，我们最近从FSHD患者和对照组的成肌细胞培养物中获得了iPS细胞。本提案的总体目标是利用多能性fshd影响细胞所代表的独特工具来加速我们对这种疾病的分子理解及其潜在的遗传治疗。为了实现这一目标，该应用程序汇集了各自领域的世界专家的合作联盟：(1) PI，一位干细胞专家，他完成了第一个胚胎干细胞的细胞治疗，并最近发现了D4Z4重复序列与肌肉形成之间的联系；(2)一位杰出的肌肉萎缩症临床医生，他对肌肉萎缩症疾病机制做出了开创性的贡献；(3)从胚胎干细胞中提取骨骼肌的世界领导者；(4)人类胚胎干细胞同源重组的领先专家。我们提出研究来解决我们认为的三个关键障碍：了解4q35.2位点的染色质机制，了解FSHD的肌源性缺陷，以及基因修复4号染色体的测试策略。

DESCRIPTION (provided by applicant): Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive myopathy affecting approximately 25,000 individuals in the United States. It is the third most common muscular dystrophy by incidence with a prevalence near or surpassing Duchenne's. The DNA lesion associated with this disease is a contraction within a series of 3.3 kb repeats (D4Z4 repeats) near the telomere of 4q. It is not understood how this contraction results in disease, however it appears to modify the chromatin configuration of 4q35.2 and this has been proposed to lead to derepression of nearby genes. In an effort to shed light on the disease mechanism and to speed a potential cell therapy, we have recently derived iPS cells from myoblast cultures taken from FSHD patients and controls. The overall goal of this proposal is to take advantage of the unique tool represented by pluripotent FSHD-affected cells to accelerate our path towards a molecular understanding of this disease and its potential genetic therapy. To address this goal, this application brings together a collaborative consortium of world experts in their respective fields: (1) the PI, a stem cell expert who accomplished the first cell therapy from ES cells, and who has recently discovered a link between the D4Z4 repeats and myogenesis, (2) a distinguished muscular dystrophy clinician who has made seminal contributions to muscular dystrophy disease mechanisms, (3) the world leader in deriving skeletal muscle from ES cells, and (4) the leading expert in homologous recombination in human ES cells. We propose studies to address what we believe are the three key roadblocks: understanding the chromatin mechanics of the 4q35.2 locus, understanding the myogenic defect in FSHD, and testing strategies to genetically repair chromosome 4.