Faculty Collaboration Database

In vivo evaluation of adeno-associated virus gene transfer in airways of mice with acute or chronic respiratory infection. Hum Gene Ther 2014 Nov;25(11):966-76

Date

08/22/2014

Pubmed ID

25144316

Pubmed Central ID

PMC4235593

DOI

10.1089/hum.2014.002

Scopus ID

2-s2.0-84910633195 (requires institutional sign-in at Scopus site)   10 Citations

Abstract

Patients with cystic fibrosis (CF) often suffer chronic lung infection with concomitant inflammation, a setting that may reduce the efficacy of gene transfer. While gene therapy development for CF often involves viral-based vectors, little is known about gene transfer in the context of an infected airway. In this study, three mouse models were established to evaluate adeno-associated virus (AAV) gene transfer in such an environment. Bordetella bronchiseptica RB50 was used in a chronic, nonlethal respiratory infection in C57BL/6 mice. An inoculum of ∼10(5) CFU allowed B. bronchiseptica RB50 to persist in the upper and lower respiratory tracts for at least 21 days. In this infection model, administration of an AAV vector on day 2 resulted in 2.8-fold reduction of reporter gene expression compared with that observed in uninfected controls. Postponement of AAV administration to day 14 resulted in an even greater (eightfold) reduction of reporter gene expression, when compared with uninfected controls. In another infection model, Pseudomonas aeruginosa PAO1 was used to infect surfactant protein D (SP-D) or surfactant protein A (SP-A) knockout (KO) mice. With an inoculum of ∼10(5) CFU, infection persisted for 2 days in the nasal cavity of either mouse model. Reporter gene expression was approximately ∼2.5-fold lower compared with uninfected mice. In the SP-D KO model, postponement of AAV administration to day 9 postinfection resulted in only a two fold reduction in reporter gene expression, when compared with expression seen in uninfected controls. These results confirm that respiratory infections, both ongoing and recently resolved, decrease the efficacy of AAV-mediated gene transfer.

Author List

Myint M, Limberis MP, Bell P, Somanathan S, Haczku A, Wilson JM, Diamond SL

Author

J Frank Wilson MD Professor Emeritus in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acute Disease
Animals
Bordetella Infections
Chronic Disease
Cystic Fibrosis
Dependovirus
Humans
Male
Mice, Inbred C57BL
Pseudomonas Infections
Respiratory Tract Infections
Transduction, Genetic