Does the use of recombinant AAV5 in pulmonary gene therapy lead to lung damage?

Abstract This study investigated whether repeated administration of recombinant adeno-associated virus type 5 (rAAV5) to the airways induces inflammatory processes in the lungs of BALB/c-mice, with mechanical and histologic changes. Saline was instilled intratracheally in the control group, and rAAV...

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Published in:	Respiratory physiology & neurobiology Vol. 168; no. 3; pp. 203 - 209
Main Authors:	Martini, S.V, Fagundes, S.S, Schmidt, A.C, Avila, M, Ornellas, D.S, Ribas, V.T, Petrs-Silva, H, Linden, R, Faffe, D.S, Guggino, S.E, Rocco, P.R.M, Zin, W.A, Morales, M.M
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 30-09-2009
Subjects:	Adeno-associated virus 5 Adeno-associated virus type 5 Airway Resistance Analysis of Variance Animals Apoptosis Disease Models, Animal Gene therapy Genetic Therapy - adverse effects Genetic Vectors - adverse effects Green Fluorescent Proteins - genetics In Situ Nick-End Labeling Male Medical Education Mice Mice, Inbred BALB C Pneumonia - etiology Pneumonia - pathology Pulmonary mechanics Pulmonary/Respiratory Respiratory Mechanics - physiology RNA, Messenger - metabolism Time Factors Vector polymorphonuclear cells equipment resistive pressure pulmonary viscoelastic/inhomogeneous pressure complementary deoxyribonucleic acid virus group adeno-associated virus control group V T Δ P1 Δ P2 GFP recombinant adeno-associated virus type 5 rAAV5 cystic fibrosis RT-PCR V pulmonary resistive pressure cDNA glyceraldehyde-3-phosphate dehydrogenase tidal volume Req· V Vector diethylpyro-carbonate-treated water reverse-transcription polymerase chain reaction AAV5 CF Est resistance of the equipment airflow DEPC adeno-associated virus type 5 ITRs PMN pulmonary elastance CTRL AAV inverted terminal repeats cystic fibrosis transmembrane conductance regulator gene green fluorescence protein VR Gene therapy GAPDH CFTR Pulmonary mechanics Req Adeno-associated virus type 5
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Summary:	Abstract This study investigated whether repeated administration of recombinant adeno-associated virus type 5 (rAAV5) to the airways induces inflammatory processes in the lungs of BALB/c-mice, with mechanical and histologic changes. Saline was instilled intratracheally in the control group, and rAAV5-green fluorescence protein (GFP) (4 × 1011 particles) in the virus group (VR). These groups were subdivided into four subgroups: one dose analyzed 3 weeks later (VR1d3w) and two doses analyzed 1 (VR2d1w), 2 (VR2d2w) and 3 weeks (VR2d3w) after the second dose. Lung morphometry, mechanical parameters, airway responsiveness, rAAV5-GFP transduction and the expression of inflammatory cytokines were investigated. No significant differences in lung mechanics, airway responsiveness, and morphometry were observed. Re-administration of rAAV5 vector resulted in a decrease in GFP mRNA expression in the VR2d3w group. There was no evidence of inflammatory response or apoptosis in any group. rAAV5 did not induce an inflammatory process, mechanical or morphometric changes in the lungs. AAV5 may be an appropriate vector for lung gene therapy.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1569-9048 1878-1519
DOI:	10.1016/j.resp.2009.06.016