title: Gel-mediated delivery of AAV1 vectors corrects ventilatory function in Pompe mice with established disease.
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 CO2 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.
authors.affiliation: Powell Gene Therapy Center, University of Florida, Gainesville, Florida 32610, USA. cmah@ufl.edu
authors.forename: Cathryn S
authors.initials: CS
authors.lastname: Mah
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Falk
authors.forename: Sean A
authors.initials: SA
authors.lastname: Germain
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Kelley
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Lewis
authors.forename: Denise A
authors.initials: DA
authors.lastname: Cloutier
authors.forename: Lara R
authors.initials: LR
authors.lastname: DeRuisseau
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Conlon
authors.forename: Kerry O
authors.initials: KO
authors.lastname: Cresawn
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Fraites
authors.forename: Martha
authors.initials: M
authors.lastname: Campbell-Thompson
authors.forename: David D
authors.initials: DD
authors.lastname: Fuller
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000737:chemistry; D000229:Dependovirus / Q000235:genetics*; D018450:Disease Progression; D005782:Gels; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006009:Glycogen Storage Disease Type II / Q000235:genetics* / Q000628:therapy*; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009136:Muscular Dystrophies / Q000235:genetics / Q000628:therapy*; D012119:Respiration; D013997:Time Factors
chemical_list: D005782:Gels; D002245:Carbon Dioxide