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Immunomodulatory, liver depot gene therapy for Pompe disease.

Authors
  • Bond, J E1
  • Kishnani, P S2
  • Koeberl, D D3
  • 1 Clinical and Translational Science Institute, Duke University, Durham, NC, USA.
  • 2 Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, NC, USA.
  • 3 Division of Medical Genetics, Department of Pediatrics, Duke University Medical School, Durham, NC, USA; Molecular Genetics and Microbiology, Duke University, Durham, NC, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cellular Immunology
Publisher
Elsevier
Publication Date
Aug 01, 2019
Volume
342
Pages
103737–103737
Identifiers
DOI: 10.1016/j.cellimm.2017.12.011
PMID: 29295737
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Pompe disease is caused by mutations in acid alpha glucosidase (GAA) that causes accumulation of lysosomal glycogen affecting the heart and skeletal muscles, and can be fatal. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) improves muscle function by reducing glycogen accumulation. Limitations of ERT include a short half-life and the formation of antibodies that result in reduced efficacy. By harnessing the immune tolerance induction properties of the liver, liver-targeted gene delivery (with an adeno-associated virus vector containing a liver specific promoter), suppresses immunity against the GAA introduced by gene therapy. This induces immune tolerance to rhGAA by activating regulatory T cells and simultaneously, corrects GAA deficiency. Potentially, liver-targeted gene therapy can be performed once with lasting effects, by administering a relatively low dose of an adeno-associated virus type 8 vector to replace and induce immune tolerance to GAA. Copyright © 2018 Elsevier Inc. All rights reserved.

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