AAV Gene Therapy Utilizing Glycosylation-Independent Lysosomal Targeting Tagged GAA in the Hypoglossal Motor System of Pompe Mice
| Autor: | David D. Fuller, Amy Poirier, Barry J. Byrne, Phillip A. Doerfler, Lauren Vaught, Michael D. Sunshine, Brendan M. Doyle, Marda Jorgensen, Darin J. Falk, Sara M.F. Turner |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities Glycosylation lcsh:QH426-470 Genetic enhancement Biology Virus Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Tongue tongue Genetics medicine Lysosomal storage disease GAA hypoglossal lcsh:QH573-671 Molecular Biology Gene motoneuron chemistry.chemical_classification Genioglossus lcsh:Cytology nutritional and metabolic diseases AAV medicine.disease respiratory Molecular biology gene therapy 3. Good health lcsh:Genetics 030104 developmental biology Enzyme medicine.anatomical_structure chemistry Pompe lysosomal storage disease genioglossus 030220 oncology & carcinogenesis Molecular Medicine |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 15, Iss, Pp 194-203 (2019) Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| Popis: | 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. Keywords: hypoglossal, tongue, Pompe, gene therapy, GAA, AAV, lysosomal storage disease, motoneuron, genioglossus, respiratory |
| Databáze: | OpenAIRE |
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