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 (L276I(KI)) 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 L276I(KI) 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.
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Chunping
authors.initials: C
authors.lastname: Qiao
authors.affiliation: 1] Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA [2] Graduate Institute of Injury Prevention and Control, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chi-Hsien
authors.initials: CH
authors.lastname: Wang
authors.affiliation: 1] Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA [2] Cardiovascular Division of Internal Medicine, Tongji Hospital, Tongji Medical college, Huazhong University of Science and Technology, Wuhan, PR China.
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zhao
authors.affiliation: McColl-Lockwood Laboratory for Muscular Dystrophy Research, Neuromuscular/ALS Center, Carolinas Medical Center, Charlotte, North Carolina, USA.
authors.forename: Peijuan
authors.initials: P
authors.lastname: Lu
authors.affiliation: McColl-Lockwood Laboratory for Muscular Dystrophy Research, Neuromuscular/ALS Center, Carolinas Medical Center, Charlotte, North Carolina, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Awano
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Li
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Carrie Bette
authors.initials: CB
authors.lastname: Martin
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.affiliation: McColl-Lockwood Laboratory for Muscular Dystrophy Research, Neuromuscular/ALS Center, Carolinas Medical Center, Charlotte, North Carolina, USA.
authors.forename: Qilong
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Xiao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D015316:Genetic Therapy / Q000379:methods*; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D009137:Muscular Dystrophy, Animal / Q000628:therapy; D010430:Pentosyltransferases; D011506:Proteins / Q000235:genetics*
chemical_list: D011506:Proteins; C443107:FKRP protein, human; D010430:Pentosyltransferases