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

点击翻译按钮获取中文摘要

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.