Muscle and heart function restoration in a limb girdle muscular dystrophy 2I (LGMD2I) mouse model by systemic FKRP gene delivery

Chunping Qiao, Chi Hsien Wang, Chunxia Zhao, Peijuan Lu, Hiroyuki Awano, Bin Xiao, Jianbin Li, Zhenhua Yuan, Yi Dai, Carrie Bette Martin, Juan Li, Qilong Lu, Xiao Xiao

Research output: Contribution to journalArticle

  • 12 Citations

Abstract

Mutations in fukutin-related protein (FKRP) gene cause a wide spectrum of disease phenotypes including the mild limb-girdle muscular dystrophy 2I (LGMD2I), the severe Walker-Warburg syndrome, and muscle-eye-brain disease. FKRP deficiency results in α-dystroglycan (α-DG) hypoglycosylation in the muscle and heart, which is a biochemical hallmark of dystroglycanopathies. To study gene replacement therapy, we generated and characterized a new mouse model of LGMD2I harboring the human mutation leucine 276 to isoleucine (L276I) in the mouse alleles. The homozygous knock-in mice (L276IKI) mimic the classic late onset phenotype of LGMD2I in both skeletal and cardiac muscles. Systemic delivery of human FKRP gene by AAV9 vector in the L276IKI mice, at either neonatal age or at the age of 9 months, rendered body wide FKRP expression and restored glycosylation of α-DG in both skeletal and cardiac muscles. FKRP gene therapy ameliorated dystrophic pathology and cardiomyopathy such as muscle degeneration, fibrosis, and myofiber membrane leakage, resulting in restoration of muscle and heart contractile functions. Thus, these results demonstrated that the treatment based on FKRP gene replacement was effective.

LanguageEnglish (US)
Pages1890-1899
Number of pages10
JournalMolecular Therapy
Volume22
Issue number11
DOIs
StatePublished - Jul 22 2014

Fingerprint

Limb-Girdle Muscular Dystrophies
Myocardium
Walker-Warburg Syndrome
Dystroglycans
Genetic Therapy
Skeletal Muscle
Proteins
Phenotype
Protein Deficiency
Mutation
Isoleucine
Cardiomyopathies
Glycosylation
Leucine
Fibrosis
Alleles
Pathology
Muscles
Membranes
Genes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Muscle and heart function restoration in a limb girdle muscular dystrophy 2I (LGMD2I) mouse model by systemic FKRP gene delivery. / Qiao, Chunping; Wang, Chi Hsien; Zhao, Chunxia; Lu, Peijuan; Awano, Hiroyuki; Xiao, Bin; Li, Jianbin; Yuan, Zhenhua; Dai, Yi; Martin, Carrie Bette; Li, Juan; Lu, Qilong; Xiao, Xiao.

In: Molecular Therapy, Vol. 22, No. 11, 22.07.2014, p. 1890-1899.

Research output: Contribution to journalArticle

Qiao, C, Wang, CH, Zhao, C, Lu, P, Awano, H, Xiao, B, Li, J, Yuan, Z, Dai, Y, Martin, CB, Li, J, Lu, Q & Xiao, X 2014, 'Muscle and heart function restoration in a limb girdle muscular dystrophy 2I (LGMD2I) mouse model by systemic FKRP gene delivery' Molecular Therapy, vol 22, no. 11, pp. 1890-1899. DOI: 10.1038/mt.2014.141
Qiao, Chunping ; Wang, Chi Hsien ; Zhao, Chunxia ; Lu, Peijuan ; Awano, Hiroyuki ; Xiao, Bin ; Li, Jianbin ; Yuan, Zhenhua ; Dai, Yi ; Martin, Carrie Bette ; Li, Juan ; Lu, Qilong ; Xiao, Xiao. / Muscle and heart function restoration in a limb girdle muscular dystrophy 2I (LGMD2I) mouse model by systemic FKRP gene delivery. In: Molecular Therapy. 2014 ; Vol. 22, No. 11. pp. 1890-1899
@article{86817607bd3040fd853c6598fe016462,
title = "Muscle and heart function restoration in a limb girdle muscular dystrophy 2I (LGMD2I) mouse model by systemic FKRP gene delivery",
abstract = "Mutations in fukutin-related protein (FKRP) gene cause a wide spectrum of disease phenotypes including the mild limb-girdle muscular dystrophy 2I (LGMD2I), the severe Walker-Warburg syndrome, and muscle-eye-brain disease. FKRP deficiency results in α-dystroglycan (α-DG) hypoglycosylation in the muscle and heart, which is a biochemical hallmark of dystroglycanopathies. To study gene replacement therapy, we generated and characterized a new mouse model of LGMD2I harboring the human mutation leucine 276 to isoleucine (L276I) in the mouse alleles. The homozygous knock-in mice (L276IKI) mimic the classic late onset phenotype of LGMD2I in both skeletal and cardiac muscles. Systemic delivery of human FKRP gene by AAV9 vector in the L276IKI mice, at either neonatal age or at the age of 9 months, rendered body wide FKRP expression and restored glycosylation of α-DG in both skeletal and cardiac muscles. FKRP gene therapy ameliorated dystrophic pathology and cardiomyopathy such as muscle degeneration, fibrosis, and myofiber membrane leakage, resulting in restoration of muscle and heart contractile functions. Thus, these results demonstrated that the treatment based on FKRP gene replacement was effective.",
author = "Chunping Qiao and Wang, {Chi Hsien} and Chunxia Zhao and Peijuan Lu and Hiroyuki Awano and Bin Xiao and Jianbin Li and Zhenhua Yuan and Yi Dai and Martin, {Carrie Bette} and Juan Li and Qilong Lu and Xiao Xiao",
year = "2014",
month = "7",
day = "22",
doi = "10.1038/mt.2014.141",
language = "English (US)",
volume = "22",
pages = "1890--1899",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - Muscle and heart function restoration in a limb girdle muscular dystrophy 2I (LGMD2I) mouse model by systemic FKRP gene delivery

AU - Qiao,Chunping

AU - Wang,Chi Hsien

AU - Zhao,Chunxia

AU - Lu,Peijuan

AU - Awano,Hiroyuki

AU - Xiao,Bin

AU - Li,Jianbin

AU - Yuan,Zhenhua

AU - Dai,Yi

AU - Martin,Carrie Bette

AU - Li,Juan

AU - Lu,Qilong

AU - Xiao,Xiao

PY - 2014/7/22

Y1 - 2014/7/22

N2 - Mutations in fukutin-related protein (FKRP) gene cause a wide spectrum of disease phenotypes including the mild limb-girdle muscular dystrophy 2I (LGMD2I), the severe Walker-Warburg syndrome, and muscle-eye-brain disease. FKRP deficiency results in α-dystroglycan (α-DG) hypoglycosylation in the muscle and heart, which is a biochemical hallmark of dystroglycanopathies. To study gene replacement therapy, we generated and characterized a new mouse model of LGMD2I harboring the human mutation leucine 276 to isoleucine (L276I) in the mouse alleles. The homozygous knock-in mice (L276IKI) mimic the classic late onset phenotype of LGMD2I in both skeletal and cardiac muscles. Systemic delivery of human FKRP gene by AAV9 vector in the L276IKI mice, at either neonatal age or at the age of 9 months, rendered body wide FKRP expression and restored glycosylation of α-DG in both skeletal and cardiac muscles. FKRP gene therapy ameliorated dystrophic pathology and cardiomyopathy such as muscle degeneration, fibrosis, and myofiber membrane leakage, resulting in restoration of muscle and heart contractile functions. Thus, these results demonstrated that the treatment based on FKRP gene replacement was effective.

AB - Mutations in fukutin-related protein (FKRP) gene cause a wide spectrum of disease phenotypes including the mild limb-girdle muscular dystrophy 2I (LGMD2I), the severe Walker-Warburg syndrome, and muscle-eye-brain disease. FKRP deficiency results in α-dystroglycan (α-DG) hypoglycosylation in the muscle and heart, which is a biochemical hallmark of dystroglycanopathies. To study gene replacement therapy, we generated and characterized a new mouse model of LGMD2I harboring the human mutation leucine 276 to isoleucine (L276I) in the mouse alleles. The homozygous knock-in mice (L276IKI) mimic the classic late onset phenotype of LGMD2I in both skeletal and cardiac muscles. Systemic delivery of human FKRP gene by AAV9 vector in the L276IKI mice, at either neonatal age or at the age of 9 months, rendered body wide FKRP expression and restored glycosylation of α-DG in both skeletal and cardiac muscles. FKRP gene therapy ameliorated dystrophic pathology and cardiomyopathy such as muscle degeneration, fibrosis, and myofiber membrane leakage, resulting in restoration of muscle and heart contractile functions. Thus, these results demonstrated that the treatment based on FKRP gene replacement was effective.

UR - http://www.scopus.com/inward/record.url?scp=84964313332&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964313332&partnerID=8YFLogxK

U2 - 10.1038/mt.2014.141

DO - 10.1038/mt.2014.141

M3 - Article

VL - 22

SP - 1890

EP - 1899

JO - Molecular Therapy

T2 - Molecular Therapy

JF - Molecular Therapy

SN - 1525-0016

IS - 11

ER -