Recombinant AAV Serotype and Capsid Mutant Comparison for Pulmonary Gene Transfer of [alpha]-1-Antitrypsin Using Invasive and Noninvasive Delivery

Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The nonin...

Full description

Saved in:
Bibliographic Details
Published inMolecular therapy Vol. 17; no. 1; p. 81
Main Authors Liqun Wang, Rejean, Mclaughlin, Thomas, Cossette, Travis, Tang, Qiushi, Foust, Kevin, Campbell-thompson, Martha, Martino, Ashley, Cruz, Pedro, Loiler, Scott, Mueller, Christian, Flotte, Terence R
Format Journal Article
LanguageEnglish
Published Milwaukee Elsevier Limited 01.01.2009
Subjects
Drug dosages
Efficiency
Enzymes
Gene expression
Gene therapy
Genomes
Ligands
Low density lipoprotein receptors
Pediatrics
Peptides
Statistical analysis
Vectors (Biology)
Viral infections
Viruses
United States > US
Massachusetts
Florida
Online AccessGet full text

Cover

More Information
Summary:Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The noninvasive intranasal delivery was compared with the traditional intratracheal lung delivery. The rAAV8 was the most efficient serotype at expressing α-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 × 10 10 vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar lavage fluid (BALF) levels of human AAT (hAAT) were about 6- and 2.5-fold higher, respectively, than those of rAAV5 group. Among the rAAV2 capsid mutants, the rAAV2 capsid mutants that display a peptide sequence from hAAT ("long serpin") indicated a twofold increase in transgene expression. For most vectors, the serum hAAT levels achieved after intranasal delivery were 1/2 to 1/3 of those with the intratracheal method. Overall, rAAV8 was the most promising vector for the future application in gene therapy of pulmonary diseases such as AAT deficiency-related emphysema.
ISSN:1525-0016
1525-0024
DOI:10.1038/mt.2008.217