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AAV Gene Therapy Utilizing Glycosylation-Independent Lysosomal Targeting Tagged GAA in the Hypoglossal Motor System of Pompe Mice.

Authors
  • Doyle, Brendan M1, 2
  • Turner, Sara M F1, 2
  • Sunshine, Michael D1, 2
  • Doerfler, Phillip A3, 4
  • Poirier, Amy E5, 2
  • Vaught, Lauren A3, 4, 2
  • Jorgensen, Marda L3
  • Falk, Darin J3, 4, 2
  • Byrne, Barry J3, 4, 2
  • Fuller, David D1, 6, 2
  • 1 Department of Physical Therapy, University of Florida, Gainesville, FL 32610, USA.
  • 2 Center for Respiratory Research and Rehabilitation, University of Florida, Gainesville, FL 32610, USA.
  • 3 Department of Pediatrics, University of Florida, Gainesville, FL 32610, USA.
  • 4 Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610, USA.
  • 5 Department of Neuroscience, University of Florida, Gainesville, FL 32610, USA.
  • 6 Mcknight Brain Institute, University of Florida, Gainesville, FL 32610, USA.
Type
Published Article
Journal
Molecular Therapy — Methods & Clinical Development
Publisher
Elsevier
Publication Date
Dec 13, 2019
Volume
15
Pages
194–203
Identifiers
DOI: 10.1016/j.omtm.2019.08.009
PMID: 31660421
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Pompe disease is caused by mutations in the gene encoding the lysosomal glycogen-metabolizing enzyme, acid-alpha glucosidase (GAA). Tongue myofibers and hypoglossal motoneurons appear to be particularly susceptible in Pompe disease. Here we used intramuscular delivery of adeno-associated virus serotype 9 (AAV9) for targeted delivery of an enhanced form of GAA to tongue myofibers and motoneurons in 6-month-old Pompe (Gaa -/- ) mice. We hypothesized that addition of a glycosylation-independent lysosomal targeting tag to the protein would result in enhanced expression in tongue (hypoglossal) motoneurons when compared to the untagged GAA. Mice received an injection into the base of the tongue with AAV9 encoding either the tagged or untagged enzyme; tissues were harvested 4 months later. Both AAV9 constructs effectively drove GAA expression in lingual myofibers and hypoglossal motoneurons. However, mice treated with the AAV9 construct encoding the modified GAA enzyme had a >200% increase in the number of GAA-positive motoneurons as compared to the untagged GAA (p < 0.008). Our results confirm that tongue delivery of AAV9-encoding GAA can effectively target tongue myofibers and associated motoneurons in Pompe mice and indicate that the effectiveness of this approach can be improved by addition of the glycosylation-independent lysosomal targeting tag. © 2019 The Authors.

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