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Facioscapulohumeral muscular dystrophy (FSHD) affects 1 in approximately 15,000 individuals worldwide. One of the obstacles in developing treatments for FSHD is the lack of a small animal model of the disease. The genetics of FSHD make it difficult, if not impossible, to make a mouse with muscles that have the same characteristics as the muscles of individuals with FSHD. This in turn has made it difficult to study mature muscle fibers with the characteristics of FSHD muscle in the laboratory, where conditions can be controlled to examine the morphological and physiological changes associated with disease and to test therapeutics that can reverse those changes. We have taken a novel approach to creating a mouse with FSHD muscles: we are transplanting human muscle precursor cells (hMPCs) from healthy and FSHD donors into mice and inducing them to form mature muscle tissue. We pretreat the mice to eliminate the major hindlimb muscle, the Tibialis anterior, and to prevent it from regenerating. We then inject hMPCs and treat the muscle with an unique set of methods to promote their survival and their ability to form new muscle of human origin. We have had great success using both normal and FSHD MPCs to form human muscle fibers in the mouse hindlimb that are mature and functional. Moreover, the muscles formed from FSHD cells express DUX4, the gene that is altered in FSHD and that is most likely to cause the disease.
Here we propose to collaborate with Fulcrum Therapeutics to generate a genetically well controlled set of grafts from cells from a mosaic patient with FSHD. The grafts will be derived from cells that carry the genetic defect associated with FSHD, or from normal cells from the same individual. We will characterize these grafts and then use them to test a new therapeutic drug developed by Fulcrum to target DUX4.