A Novel Xenograft Mouse Model of Facioscapulohumeral Muscular Dystrophy

Principal Investigator: Kathryn Wagner

Despite being one of the most prevalent neuromuscular disorders worldwide, there have been very few clinical trials in Facioscapulohumeral muscular dystrophy (FSHD). Currently there are no clinical trials and no good therapeutic options for this progressively disabling disease. One of the main impediments to the development of novel drugs for FSHD is the lack of an accepted animal model stemming from an incomplete understanding of the pathogenesis of the disease.

This application proposes to develop a novel animal model of FSHD which is independent of any hypothesis of pathogenesis. In this model, muscle tissue from subjects with FSHD are transplanted into the hindlimbs of immunodeficient, NOD-Rag1null IL2ry null mice. Preliminary data indicate that these xenografts are vascularized and innervated by the mouse host. Human myoblasts fully regenerate the tissue with new myofibers which survive in vivo through 20 weeks post transplantation. Feasibility has been established with dozens of recent and prospective human donors and the ability to generate approximately 20 xenografts from a single open muscle biopsy.

The first aim of this proposal is to optimize the xenograft by determining the maximal size of human graft which is viable in this model and the minimum amount of time from transplantation until full regeneration of the human graft in the mouse host. Use of nerve translocation as well as myostatin inhibition to optimize the graft will be critically assessed.

The second aim of the proposal is to validate the xenograft as a model of FSHD and to fully characterize it for future use in preclinical studies. In this aim, grafts will be evaluated for thir histopathological, physiologic and molecular (gene expression) characteristics. FSHD xenografts will be compared to the biopsy specimen from which they originated and to xenografts of normal muscle from biologically related donors. The product of this work will be a fully characterized xenograft model of FSHD as well as standard operating procedures for evaluating this model in preclinical drug studies. Such studies are expected to facilitate entry of novel therapeutics into clinical trials for FSHD which is currently an underserved disease population.