Modeling Pulmonary Disease Pathways Using Recombinant Adeno-Associated Virus 6.2.
Viral vectors have been applied successfully to generate disease-related animal models and to functionally characterize target genes in vivo. However, broader application is still limited by complex vector production, biosafety requirements, and vector-mediated immunogenic responses, possibly interfering with disease-relevant pathways. Here, we describe adeno-associated virus (AAV) variant 6.2 as an ideal vector for lung delivery in mice, overcoming most of the aforementioned limitations. In a proof-of-concept study using AAV6.2 vectors expressing IL-13 and transforming growth factor-β1 (TGF-β1), we were able to induce hallmarks of severe asthma and pulmonary fibrosis, respectively. Phenotypic characterization and deep sequencing analysis of the AAV-IL-13 asthma model revealed a characteristic disease signature. Furthermore, suitability of the model for compound testing was also demonstrated by pharmacological intervention studies using an anti-IL-13 antibody and dexamethasone. Similarly, the AAV-TGF-β1 fibrosis model showed several disease-like pathophenotypes monitored by micro-computed tomography imaging and lung function measurement. Most importantly, analyses using stuffer control vectors demonstrated that in contrast to a common adenovirus-5 vector, AAV6.2 vectors did not induce any measurable inflammation and therefore carry a lower risk of altering relevant readouts. In conclusion, we propose AAV6.2 as an ideal vector system for the functional characterization of target genes in the context of pulmonary diseases in mice.
['Strobel|Benjamin|B|', 'Duechs|Matthias J|MJ|', 'Schmid|Ramona|R|', 'Stierstorfer|Birgit E|BE|', 'Bucher|Hannes|H|', 'Quast|Karsten|K|', 'Stiller|Detlef|D|', 'Hildebrandt|Tobias|T|', 'Mennerich|Detlev|D|', 'Gantner|Florian|F|', 'Erb|Klaus J|KJ|', 'Kreuz|Sebastian|S|']
D000818:Animals D001249:Asthma D000229:Dependovirus D004195:Disease Models, Animal D005260:Female D005822:Genetic Vectors D054990:Idiopathic Pulmonary Fibrosis D018793:Interleukin-13 D008807:Mice, Inbred BALB C D014161:Transduction, Genetic D053773:Transforming Growth Factor beta1
animal models IL-13 TGF-β1 asthma lung fibrosis