Suppression of pullulanase-induced cytotoxic T cell response with a dual promoter in GSD IIIa mice.

dc.contributor.author

Lim, Jeong-A

dc.contributor.author

Kishnani, Priya S

dc.contributor.author

Sun, Baodong

dc.date.accessioned

2023-06-01T14:34:27Z

dc.date.available

2023-06-01T14:34:27Z

dc.date.issued

2022-12

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2023-06-01T14:34:26Z

dc.description.abstract

Glycogen debranching enzyme deficiency in glycogen storage disease type III (GSD III) results in excessive glycogen accumulation in multiple tissues, primarily the liver, heart, and skeletal muscle. We recently reported that an adeno-associated virus vector expressing a bacterial debranching enzyme (pullulanase) driven by the ubiquitous CMV enhancer/chicken β-actin (CB) promoter cleared glycogen in major affected tissues of infant GSD IIIa mice. In this study, we developed a potentially novel dual promoter consisting of a liver-specific promoter (LSP) and the CB promoter for gene therapy in adult GSD IIIa mice. Ten-week treatment with an adeno-associated virus vector containing the LSP-CB dual promoter in adult GSD IIIa mice significantly increased pullulanase expression and reduced glycogen contents in the liver, heart, and skeletal muscle, accompanied by the reversal of liver fibrosis, improved muscle function, and a significant decrease in plasma biomarkers alanine aminotransferase, aspartate aminotransferase, and creatine kinase. Compared with the CB promoter, the dual promoter effectively decreased pullulanase-induced cytotoxic T lymphocyte responses and enabled persistent therapeutic gene expression in adult GSD IIIa mice. Future studies are needed to determine the long-term durability of dual promoter-mediated expression of pullulanase in adult GSD IIIa mice and in large animal models.

dc.identifier

152970

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2379-3708

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2379-3708

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https://hdl.handle.net/10161/27500

dc.language

eng

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American Society for Clinical Investigation

dc.relation.ispartof

JCI insight

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10.1172/jci.insight.152970

dc.subject

T-Lymphocytes, Cytotoxic

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Animals

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Mice

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Glycogen Storage Disease Type III

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Glycogen

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Genetic Therapy

dc.title

Suppression of pullulanase-induced cytotoxic T cell response with a dual promoter in GSD IIIa mice.

dc.type

Journal article

duke.contributor.orcid

Kishnani, Priya S|0000-0001-8251-909X

duke.contributor.orcid

Sun, Baodong|0000-0002-2191-0025

pubs.begin-page

e152970

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23

pubs.organisational-group

Duke

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School of Medicine

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Basic Science Departments

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Clinical Science Departments

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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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Duke Clinical Research Institute

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Institutes and Provost's Academic Units

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Initiatives

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Duke Innovation & Entrepreneurship

pubs.publication-status

Published

pubs.volume

7

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