Gel-mediated delivery of AAV1 vectors corrects ventilatory function in pompe mice with established disease

Cathryn S. Mah, Darin J. Falk, Sean A. Germain, Jeffry S. Kelley, Melissa A. Lewis, Denise A. Cloutier, Lara R. Deruisseau, Thomas J. Conlon, Kerry O. Cresawn, Thomas J. Fraites, Martha Campbell-Thompson, David D. Fuller, Barry J. Byrne

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

Pompe disease is a muscular dystrophy that results in respiratory insufficiency. We characterized the outcomes of targeted delivery of recombinant adeno-associated virus serotype 1 (rAAV2/1) vector to diaphragms of Pompe mice with varying stages of disease progression. We observed significant improvement in diaphragm contractile strength in mice treated at 3 months of age that is sustained at least for 1 year and enhanced contractile strength in mice treated at 9 and 21 months of age, measured 3 months post-treatment. Ventilatory parameters including tidal volume/inspiratory time ratio, minute ventilation/expired CO 2 ratio, and peak inspiratory airflow were significantly improved in mice treated at 3 months and tested at 6 months. Despite early improvement, mice treated at 3 months and tested at 1 year had diminished normoxic ventilation, potentially due to attenuation of correction over time or progressive degeneration of nontargeted accessory tissues. However, for all rAAV2/1-treated mice (treated at 3, 9, and 21 months, assayed 3 months later; treated at 3 months, assayed at 1 year), minute ventilation and peak inspiratory flows were significantly improved during respiratory challenge. These results demonstrate that gel-mediated delivery of rAAV2/1 vectors can significantly augment ventilatory function at initial and late phases of disease in a model of muscular dystrophy.

Original languageEnglish (US)
Pages (from-to)502-510
Number of pages9
JournalMolecular Therapy
Volume18
Issue number3
DOIs
StatePublished - Mar 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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