Key result
Intrapleural administration of an AAV5-halpha1AT vector in mice mediated serum alpha1AT levels of 900 +/- 50 microg/ml at 40 weeks, 10-fold higher than AAV2 delivery.
Why the study?
Does intrapleural administration of AAV vectors expressing human alpha1-antitrypsin improve lung and serum levels of alpha1AT compared to intramuscular delivery in C57BL/6 mice?
Does intrapleural administration of AAV vectors expressing human alpha1-antitrypsin improve lung and serum levels of alpha1AT compared to intramuscular delivery in C57BL/6 mice?
Effect estimate: 10-fold higher
Intrapleural administration of AAV5 vectors expressing alpha1-antitrypsin achieves sustained, therapeutic serum and lung levels in mice, suggesting a potential gene therapy strategy for alpha1-antitrypsin deficiency.
Sustained high alpha1AT levels via intrapleural AAV5 in mice; leaves open translation to safe, effective therapy in alpha1AT deficiency.
alpha1-Antitrypsin (alpha1AT) is a serine proteinase inhibitor that protects the lung from degradation by neutrophil proteases. In alpha1AT deficiency, an autosomal recessive disorder resulting from mutations in the alpha1AT (approved symbol SERPINA1) gene, serum alpha1AT levels of < 570 microg/ml are associated with development of emphysema. Adeno-associated virus (AAV) serotype 2 (AAV2) vectors expressing alpha1AT administered intramuscularly or intravenously mediate sustained serum levels of alpha1AT in experimental animals. Since the lung is only 2% of the body weight, AAV vector delivery to the muscle or liver is inefficient, as most of the alpha1AT does not reach the lung. The present study evaluates AAV2- and AAV5-mediated delivery of human alpha1AT (halpha1AT) to C57BL/6 mice using the intrapleural space as a platform for local production of alpha1AT. Intrapleural administration of either an AAV5-halpha1AT or an AAV2-halpha1AT vector achieves higher lung and serum levels of alpha1AT than intramuscular delivery. AAV5-mediated serum and lung alpha1AT levels were 10-fold higher than those achieved by AAV2 delivery via either route. The diaphragm, lung, and heart are the major sites of transgene expression following intrapleural administration of an AAV5 reporter vector. At 40 weeks postadministration, intrapleural administration of the AAV5-halpha1AT vector mediated serum alpha1AT levels of 900 +/- 50 microg/ml, 1.6-fold higher than the accepted therapeutic level of 570 microg/ml. In the context that the pleura is a safe site for administration, intrapleural administration using AAV5 vectors may represent an attractive gene therapy strategy for alpha1AT deficiency in humans.
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De et al. (2004) studied alpha1-Antitrypsin deficiency. Intrapleural administration of AAV5-halpha1AT vector vs. Intramuscular delivery or AAV2 delivery was evaluated on Serum and lung alpha1AT levels (10-fold higher). Intrapleural administration of an AAV5-halpha1AT vector in mice mediated serum alpha1AT levels of 900 +/- 50 microg/ml at 40 weeks, 10-fold higher than AAV2 delivery.
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