Adeno-associated virus serotype 9 vectors transduce murine alveolar and nasal epithelia and can be readministered.
Airway-directed gene transfer has emerged as a promising approach for the treatment of the two genetic diseases of the lung, namely cystic fibrosis and alpha-1-antitrypsin deficiency. Herein we describe the transduction efficiency of a novel adeno-associated virus (AAV) vector, AAV2/9, across murine nasal and lung airway epithelia. At the peak of gene expression AAV2/9-mediated human alpha-1-antitrypsin gene expression in serum was approximately 60-fold better than that of AAV2/5. We found that AAV2/9-mediated nLacZ gene transfer in nasal and lung airways was relatively stable for 9 months, suggesting that a progenitor airway cell population was transduced. Most interestingly, we show that AAV2/9 can be readministered in the presence of high levels of serum-circulating neutralizing antibodies as early as 1 month after initial exposure, with minimal effect on overall reporter gene expression, rendering it a promising gene transfer vector candidate for use in humans.
Limberis
Maria P
MP
Gene Therapy Program, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
Wilson
James M
JM
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D002454:Cell Differentiation; D002645:Chickens; D000229:Dependovirus / Q000145:classification / Q000235:genetics* / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics*; D016679:Genome, Viral / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D009297:Nasal Mucosa / Q000166:cytology; D011650:Pulmonary Alveoli / Q000166:cytology / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D012703:Serotyping; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*; D019076:Transgenes / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism
D000515:alpha 1-Antitrypsin; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D001616:beta-Galactosidase