TY - JOUR
T1 - Humanskeletal musclexenograft as anewpreclinical model for muscle disorders
AU - Zhang, Yuanfan
AU - King, Oliver D.
AU - Rahimov, Fedik
AU - Jones, Takako I.
AU - Ward, Christopher W.
AU - Kerr, Jaclyn P.
AU - Liu, Naili
AU - Emerson, Charles P.
AU - Kunkel, Louis M.
AU - Partridge, Terence A.
AU - Wagner, Kathryn R.
N1 - Funding Information:
This work was supported by the National Institutes of Health (NIH) (1R21NS079529 to K.R.W., U54HD060848 to C.P.E.) and the Muscular Dystrophy Association (216652 to C.P.E., 202863 to F.R.). This work was also made possible by the National Center for Research Resources (NCRR) a component of the NIH, and NIH Roadmap for Medical Research (UL1 RR 025005). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.
PY - 2014/6/15
Y1 - 2014/6/15
N2 - Development of novel therapeutics requires good animal models of disease. Disorders for which good animal models do not exist have very few drugs in development or clinical trial. Even where there are accepted, albeit imperfect models, the leap from promising preclinical drug results to positive clinical trials commonly fails, including in disorders of skeletal muscle. The main alternative model for early drug development, tissue culture, lacks both the architecture and, usually, the metabolic fidelity of the normal tissue in vivo. Herein, we demonstrate the feasibility and validity ofhuman to mouse xenografts as a preclinicalmodel ofmyopathy.Human skeletal muscle biopsies transplanted into the anterior tibial compartment of the hindlimbs of NOD-Rag1null IL2rγnull 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 amodel of facioscapulohumeral muscular dystrophy is demonstrated in disease biomarker studies, showing that gene expression profiles of xenografts mirror those of the fresh donor biopsies. These findings illustrate the value of a new experimental model of muscle disease, the human muscle xenograft in mice, 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.
AB - Development of novel therapeutics requires good animal models of disease. Disorders for which good animal models do not exist have very few drugs in development or clinical trial. Even where there are accepted, albeit imperfect models, the leap from promising preclinical drug results to positive clinical trials commonly fails, including in disorders of skeletal muscle. The main alternative model for early drug development, tissue culture, lacks both the architecture and, usually, the metabolic fidelity of the normal tissue in vivo. Herein, we demonstrate the feasibility and validity ofhuman to mouse xenografts as a preclinicalmodel ofmyopathy.Human skeletal muscle biopsies transplanted into the anterior tibial compartment of the hindlimbs of NOD-Rag1null IL2rγnull 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 amodel of facioscapulohumeral muscular dystrophy is demonstrated in disease biomarker studies, showing that gene expression profiles of xenografts mirror those of the fresh donor biopsies. These findings illustrate the value of a new experimental model of muscle disease, the human muscle xenograft in mice, 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.
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U2 - 10.1093/hmg/ddu028
DO - 10.1093/hmg/ddu028
M3 - Article
C2 - 24452336
AN - SCOPUS:84901354846
SN - 0964-6906
VL - 23
SP - 3180
EP - 3188
JO - Human molecular genetics
JF - Human molecular genetics
IS - 12
ER -