Antibody formation and mannose-6-phosphate receptor expression impact the efficacy of muscle-specific transgene expression in murine Pompe disease.

dc.contributor.author

Sun, Baodong

dc.contributor.author

Li, Songtao

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Bird, Andrew

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Yi, Haiqing

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Kemper, Alex

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Thurberg, Beth L

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Koeberl, Dwight D

dc.coverage.spatial

England

dc.date.accessioned

2017-07-24T14:45:26Z

dc.date.available

2017-07-24T14:45:26Z

dc.date.issued

2010-11

dc.description.abstract

BACKGROUND: Lysosomal storage disorders such as Pompe disease can be more effectively treated, if immune tolerance to enzyme or gene replacement therapy can be achieved. Alternatively, immune responses against acid α-glucosidase (GAA) might be evaded in Pompe disease through muscle-specific expression of GAA with adeno-associated virus (AAV) vectors. METHODS: An AAV vector containing the MHCK7 regulatory cassette to drive muscle-specific GAA expression was administered to GAA knockout (KO) mice, immune tolerant GAA-KO mice and mannose-6-phosphate deficient GAA-KO mice. GAA activity and glycogen content were analyzed in striated muscle to determine biochemical efficacy. RESULTS: The biochemical efficacy from GAA expression was slightly reduced in GAA-KO mice, as demonstrated by higher residual glycogen content in skeletal muscles. Next, immune tolerance to GAA was induced in GAA-KO mice by co-administration of a second AAV vector encoding liver-specific GAA along with the AAV vector encoding muscle-specific GAA. Antibody formation was prevented by liver-specific GAA, and the biochemical efficacy of GAA expression was improved in the absence of antibodies, as demonstrated by significantly reduced glycogen content in the diaphragm. Efficacy was reduced in old GAA-KO mice despite the absence of antibodies. The greatest impact upon gene therapy was observed in GAA-KO mice lacking the mannose-6-phosphate receptor in muscle. The clearance of stored glycogen was markedly impaired despite high GAA expression in receptor-deficient Pompe disease mice. CONCLUSIONS: Overall, antibody formation had a subtle effect upon efficacy, whereas the absence of mannose-6-phosphate receptors markedly impaired muscle-targeted gene therapy in murine Pompe disease.

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/20967919

dc.identifier.eissn

1521-2254

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https://hdl.handle.net/10161/15091

dc.language

eng

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Wiley

dc.relation.ispartof

J Gene Med

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10.1002/jgm.1511

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Animals

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Antibody Formation

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Dependovirus

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Disease Models, Animal

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Gene Expression Regulation

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Genetic Therapy

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Genetic Vectors

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Glycogen

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Glycogen Storage Disease Type II

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Mice

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Mice, Knockout

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Muscle, Skeletal

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Receptor, IGF Type 2

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Transgenes

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alpha-Glucosidases

dc.title

Antibody formation and mannose-6-phosphate receptor expression impact the efficacy of muscle-specific transgene expression in murine Pompe disease.

dc.type

Journal article

duke.contributor.orcid

Sun, Baodong|0000-0002-2191-0025

duke.contributor.orcid

Koeberl, Dwight D|0000-0003-4513-2464

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/20967919

pubs.begin-page

881

pubs.end-page

891

pubs.issue

11

pubs.organisational-group

Basic Science Departments

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Clinical Science Departments

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Community and Family Medicine

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Duke

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Duke Clinical Research Institute

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Institutes and Centers

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Molecular Genetics and Microbiology

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Pediatrics

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Pediatrics, Medical Genetics

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Pediatrics, Primary Care Pediatrics

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School of Medicine

pubs.publication-status

Published

pubs.volume

12

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