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.
Project Narative (Public Health Relevance) FSHD is a common and debilitating neuromuscular disease for which the genetic mutation has been identified, but for which there is no treatment because the mechanism leading to disease is not understood. Using induced pluripotent cells that we have derived from FSHD patient cells, our work aims (1) to link the genetic mutation to the disease through a defined molecular mechanism which should provide a roadmap to a rational pharmacological intervention, and (2) to test the feasibility of genetic cure of the disease in cells for the purpose of developing an autologous cell therapy.
| Hartweck, Lynn M; Anderson, Lindsey J; Lemmers, Richard J et al. (2013) A focal domain of extreme demethylation within D4Z4 in FSHD2. Neurology 80:392-9 |
| Darabi, Radbod; Arpke, Robert W; Irion, Stefan et al. (2012) Human ES- and iPS-derived myogenic progenitors restore DYSTROPHIN and improve contractility upon transplantation in dystrophic mice. Cell Stem Cell 10:610-9 |
| Dejosez, Marion; Zwaka, Thomas P (2012) Pluripotency and nuclear reprogramming. Annu Rev Biochem 81:737-65 |
