Recombinant AAV serotype and capsid mutant comparison for pulmonary gene transfer of alpha-1-antitrypsin using invasive and noninvasive delivery
Authors
Liqun Wang, RejeanMcLaughlin, Thomas J.
Cossette, Travis
Tang, Qiushi
Foust, Kevin
Campbell-Thompson, Martha
Martino, Ashley
Cruz, Pedro
Loiler, Scott A.
Mueller, Christian
Flotte, Terence R.
Document Type
Journal ArticlePublication Date
2009-01-23Keywords
AnimalsCapsid
Dependovirus
Enzyme-Linked Immunosorbent Assay
*Gene Transfer Techniques
Genetic Vectors
Lung
Mice
Mice, Inbred C57BL
Polymerase Chain Reaction
alpha 1-Antitrypsin
Allergy and Immunology
Genetics and Genomics
Pediatrics
Respiratory Tract Diseases
Metadata
Show full item recordAbstract
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 alpha-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 x 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.Source
Mol Ther. 2009 Jan;17(1):81-7. Epub 2008 Oct 21. Link to article on publisher's siteDOI
10.1038/mt.2008.217Permanent Link to this Item
http://hdl.handle.net/20.500.14038/43822PubMed ID
18941444Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1038/mt.2008.217