Adeno-associated Virus 9 mediated FKRP gene therapy restores functional glycosylation of α-dystroglycan and improves muscle functions

Lei Xu, Pei Juan Lu, Chi Hsien Wang, Elizabeth Keramaris, Chunping Qiao, Bin Xiao, Derek J. Blake, Xiao Xiao, Qi Long Lu

Research output: Contribution to journalArticle

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Abstract

Mutations in the FKRP gene are associated with a wide range of muscular dystrophies from mild limb-girdle muscular dystrophy (LGMD) 2I to severe Walker-Warburg syndrome and muscle-eye-brain disease. The characteristic biochemical feature of these diseases is the hypoglycosylation of α-dystroglycan (α-DG). Currently there is no effective treatment available. In this study, we examined the adeno-associated virus serotype 9 vector (AAV9)-mediated gene therapy in the FKRP mutant mouse model with a proline to leucine missense mutation (P448L). Our results showed that intraperitoneal administration of AAV9-FKRP resulted in systemic FKRP expression in all striated muscles examined with the highest levels in cardiac muscle. Consistent with our previous observations, FKRP protein is localized in the Golgi apparatus in myofibers. Expression of FKRP consequently restored functional glycosylation of α-DG in the skeletal and cardiac muscles. Significant improvement in dystrophic pathology, serum creatine kinase levels and muscle function was observed. Only limited FKRP transgene expression was detected in kidney and liver with no detectable toxicity. Our results provided evidence for the utility of AAV-mediated gene replacement therapy for FKRP-related muscular dystrophies.

LanguageEnglish (US)
Pages1832-1840
Number of pages9
JournalMolecular Therapy
Volume21
Issue number10
DOIs
StatePublished - Oct 1 2013

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Walker-Warburg Syndrome
Dystroglycans
Dependovirus
Muscular Dystrophies
Glycosylation
Genetic Therapy
Myocardium
Limb-Girdle Muscular Dystrophies
MM Form Creatine Kinase
Muscles
Striated Muscle
Golgi Apparatus
Missense Mutation
Transgenes
Proline
Leucine
Skeletal Muscle
Pathology
Kidney
Mutation

ASJC Scopus subject areas

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

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Adeno-associated Virus 9 mediated FKRP gene therapy restores functional glycosylation of α-dystroglycan and improves muscle functions. / Xu, Lei; Lu, Pei Juan; Wang, Chi Hsien; Keramaris, Elizabeth; Qiao, Chunping; Xiao, Bin; Blake, Derek J.; Xiao, Xiao; Lu, Qi Long.

In: Molecular Therapy, Vol. 21, No. 10, 01.10.2013, p. 1832-1840.

Research output: Contribution to journalArticle

Xu, Lei ; Lu, Pei Juan ; Wang, Chi Hsien ; Keramaris, Elizabeth ; Qiao, Chunping ; Xiao, Bin ; Blake, Derek J. ; Xiao, Xiao ; Lu, Qi Long. / Adeno-associated Virus 9 mediated FKRP gene therapy restores functional glycosylation of α-dystroglycan and improves muscle functions. In: Molecular Therapy. 2013 ; Vol. 21, No. 10. pp. 1832-1840
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abstract = "Mutations in the FKRP gene are associated with a wide range of muscular dystrophies from mild limb-girdle muscular dystrophy (LGMD) 2I to severe Walker-Warburg syndrome and muscle-eye-brain disease. The characteristic biochemical feature of these diseases is the hypoglycosylation of α-dystroglycan (α-DG). Currently there is no effective treatment available. In this study, we examined the adeno-associated virus serotype 9 vector (AAV9)-mediated gene therapy in the FKRP mutant mouse model with a proline to leucine missense mutation (P448L). Our results showed that intraperitoneal administration of AAV9-FKRP resulted in systemic FKRP expression in all striated muscles examined with the highest levels in cardiac muscle. Consistent with our previous observations, FKRP protein is localized in the Golgi apparatus in myofibers. Expression of FKRP consequently restored functional glycosylation of α-DG in the skeletal and cardiac muscles. Significant improvement in dystrophic pathology, serum creatine kinase levels and muscle function was observed. Only limited FKRP transgene expression was detected in kidney and liver with no detectable toxicity. Our results provided evidence for the utility of AAV-mediated gene replacement therapy for FKRP-related muscular dystrophies.",
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