Human skeletal muscle xenograft as a new preclinical model for muscle disorders.
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 of human to mouse xenografts as a preclinical model of myopathy. Human skeletal muscle biopsies transplanted into the anterior tibial compartment of the hindlimbs of NOD-Rag1(null) IL2rγ(null) 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 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.
The Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA Graduate Program in Cellular and Molecular Medicine and.
Yuanfan
Y
Zhang
Wellstone Program, Departments of Cell and Developmental Biology and Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Oliver D
OD
King
Program in Genomics, Division of Genetics, and.
Fedik
F
Rahimov
Wellstone Program, Departments of Cell and Developmental Biology and Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Takako I
TI
Jones
University of Maryland School of Nursing, Baltimore, MD 21201, USA.
Christopher W
CW
Ward
Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA and.
Jaclyn P
JP
Kerr
The Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA.
Naili
N
Liu
Wellstone Program, Departments of Cell and Developmental Biology and Neurology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Charles P
CP
Emerson
Program in Genomics, Division of Genetics, and The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Louis M
LM
Kunkel
Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA.
Terence A
TA
Partridge
The Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD 21205, USA Graduate Program in Cellular and Molecular Medicine and Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA wagnerk@kennedykrieger.org.
Kathryn R
KR
Wagner
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D064593:Heterografts / Q000502:physiology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D018482:Muscle, Skeletal / Q000473:pathology / Q000637:transplantation*; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000473:pathology / Q000601:surgery*
D005819:Genetic Markers