THERAPEUTIC DEVELOPMENT FOR FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY UTILIZING A NOVEL HUMAN SKELETAL MUSCLE XENOGRAFT MODEL
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Genetic muscle disorders such as facioscapulohumeral muscular dystrophy (FSHD) deprive patients of their physical strength and quality of life. Animal models have been indispensable in the research investigation and therapeutic development for genetic muscle disorders. But the successful leap from bench to bedside rarely happens because the animal model is not human and cannot predict human response to therapy precisely. Herein, we try to create a ‘living and breathing’ human muscle inside a mouse host and demonstrate the feasibility and validity of human to mouse xenografts as a preclinical model of myopathy. Human skeletal muscle biopsies as well as autopsies transplanted into the anterior tibial compartment of the hindlimbs of NOD-Rag1null IL2rγnull (NRG) immunodeficient host mice regenerate new vascularized and innervated myofibers from human myogenic precursor cells. The grafts exhibit contractile and calcium release behavior, characteristic of functional muscle tissue. The validity of the human graft as a model of FSHD is demonstrated in disease biomarker studies, showing that gene expression profiles of xenografts mirror those of the donor muscles. These findings illustrate the value of a new experimental model of muscle disease as a feasible and valid preclinical tool to better investigate the pathogenesis of human genetic myopathies and to more accurately predict their response to novel therapeutics. We also report a proof-of-concept study using antisense phosphorodiamidate morpholino oligonucleotides (PMOs) to suppress DUX4 expression, which is believed to be the causative genetic defect of FSHD currently, in FSHD myotubes and xenografts derived from patients. The most effective PMO FM10 had no significant cell toxicity. RNA-seq analyses of FSHD and control myotubes revealed that FM10 down-regulated many transcriptional targets of DUX4, without overt off-target effects. Treatment with FM10 in FSHD patient muscle xenografts also down-regulated DUX4 and DUX4 targets. These findings demonstrate the potential of antisense PMOs as an FSHD therapeutic option.