Humanskeletal musclexenograft as anewpreclinical model for muscle disorders

Yuanfan Zhang, Oliver D. King, Fedik Rahimov, Takako I. Jones, Christopher W. Ward, Jaclyn P. Kerr, Naili Liu, Charles P. Emerson, Louis M. Kunkel, Terence A. Partridge, Kathryn Rae Wagner

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3180-3188
Number of pages9
JournalHuman Molecular Genetics
Volume23
Issue number12
DOIs
StatePublished - 2014

Fingerprint

Muscular Diseases
Heterografts
Muscles
Skeletal Muscle
Facioscapulohumeral Muscular Dystrophy
Clinical Trials
Pharmaceutical Preparations
Transplants
Biopsy
Animal Disease Models
Medical Genetics
Hindlimb
Transcriptome
Theoretical Models
Animal Models
Biomarkers
Calcium
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)

Cite this

Zhang, Y., King, O. D., Rahimov, F., Jones, T. I., Ward, C. W., Kerr, J. P., ... Wagner, K. R. (2014). Humanskeletal musclexenograft as anewpreclinical model for muscle disorders. Human Molecular Genetics, 23(12), 3180-3188. https://doi.org/10.1093/hmg/ddu028

Humanskeletal musclexenograft as anewpreclinical model for muscle disorders. / Zhang, Yuanfan; King, Oliver D.; Rahimov, Fedik; Jones, Takako I.; Ward, Christopher W.; Kerr, Jaclyn P.; Liu, Naili; Emerson, Charles P.; Kunkel, Louis M.; Partridge, Terence A.; Wagner, Kathryn Rae.

In: Human Molecular Genetics, Vol. 23, No. 12, 2014, p. 3180-3188.

Research output: Contribution to journalArticle

Zhang, Y, King, OD, Rahimov, F, Jones, TI, Ward, CW, Kerr, JP, Liu, N, Emerson, CP, Kunkel, LM, Partridge, TA & Wagner, KR 2014, 'Humanskeletal musclexenograft as anewpreclinical model for muscle disorders', Human Molecular Genetics, vol. 23, no. 12, pp. 3180-3188. https://doi.org/10.1093/hmg/ddu028
Zhang Y, King OD, Rahimov F, Jones TI, Ward CW, Kerr JP et al. Humanskeletal musclexenograft as anewpreclinical model for muscle disorders. Human Molecular Genetics. 2014;23(12):3180-3188. https://doi.org/10.1093/hmg/ddu028
Zhang, Yuanfan ; King, Oliver D. ; Rahimov, Fedik ; Jones, Takako I. ; Ward, Christopher W. ; Kerr, Jaclyn P. ; Liu, Naili ; Emerson, Charles P. ; Kunkel, Louis M. ; Partridge, Terence A. ; Wagner, Kathryn Rae. / Humanskeletal musclexenograft as anewpreclinical model for muscle disorders. In: Human Molecular Genetics. 2014 ; Vol. 23, No. 12. pp. 3180-3188.
@article{dc9ffe5ea3df42ee83ad450bb6197bea,
title = "Humanskeletal musclexenograft as anewpreclinical model for muscle disorders",
abstract = "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.",
author = "Yuanfan Zhang and King, {Oliver D.} and Fedik Rahimov and Jones, {Takako I.} and Ward, {Christopher W.} and Kerr, {Jaclyn P.} and Naili Liu and Emerson, {Charles P.} and Kunkel, {Louis M.} and Partridge, {Terence A.} and Wagner, {Kathryn Rae}",
year = "2014",
doi = "10.1093/hmg/ddu028",
language = "English (US)",
volume = "23",
pages = "3180--3188",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "12",

}

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 Rae

PY - 2014

Y1 - 2014

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.

UR - http://www.scopus.com/inward/record.url?scp=84901354846&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901354846&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddu028

DO - 10.1093/hmg/ddu028

M3 - Article

C2 - 24452336

AN - SCOPUS:84901354846

VL - 23

SP - 3180

EP - 3188

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 12

ER -