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Journal of Virology, November 2004, p. 12355-12365, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12355-12365.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Secretion of a TNFR:Fc Fusion Protein following Pulmonary Administration of Pseudotyped Adeno-Associated Virus Vectors

Ziv Sandalon,{dagger} Elizabeth M. Bruckheimer,{dagger},{ddagger} Kurt H. Lustig, Linda C. Rogers, Richard W. Peluso, and Haim Burstein*

Targeted Genetics Corporation, Seattle, Washington

Received 12 May 2004/ Accepted 26 June 2004

This study evaluated and compared delivery of the tumor necrosis factor alpha receptor (TNFR)-immunoglobulin G1 (IgG1) Fc fusion (TNFR:Fc) gene to the lung by single and repeat administrations of multiple pseudotyped adeno-associated virus (AAV) vectors as a means for achieving systemic distribution of the soluble TNFR:Fc protein. A single endotracheal administration of AAV[2/5]cytomegalovirus (CMV)-TNFR:Fc vector (containing the AAV2 inverted terminal repeats and AAV5 capsid) to the rat lung resulted in long-term, high levels of serum TNFR:Fc protein that gradually declined over a period of 8 months. Endotracheal delivery of AAV[2/1]CMV-TNFR:Fc resulted in serum TNFR:Fc protein levels that were detectable for at least 4 months but were 10-fold lower than that of the AAV[2/5] vector. In contrast, secretion of the TNFR:Fc protein following pulmonary delivery of AAV[2/2]CMV-TNFR:Fc vector was very inefficient, and the protein was detected in the blood only when an airway epithelial cell-specific promoter, CC10, was substituted for the CMV enhancer/promoter to control transgene expression. In the context of AAV[2/5], the CC10 promoter was as efficient as CMV enhancer/promoter in generating similar levels of systemic TNFR:Fc protein, suggesting that this protein is secreted primarily from the airway epithelium. In mice, comparable long-term secretion of TNFR:Fc protein was demonstrated after AAV[2/2] and AAV[2/5] delivery, although the kinetics of transduction appeared to be different. All pseudotyped AAV vectors elicited serum anti-AAV capsid-neutralizing antibody responses, but these did not prevent lung transduction and efficient secretion of TNFR:Fc protein to the circulation following readministration with AAV[2/5]. These results highlight the potential utility of AAV vectors containing serotype 5 capsid to deliver and redeliver genes of secreted proteins to the lung to achieve long-term systemic protein expression.

* Corresponding author. Mailing address: Targeted Genetics Corporation, 1100 Olive Way, Suite 100, Seattle, WA 98101-1844. Phone: (206) 521-7832. Fax: (206) 521-4782. E-mail: burstein{at}targen.com.

{dagger} These authors contributed equally to this publication.

{ddagger} Present address: MedImmune, Inc., Gaithersburg, MD 20878.

Journal of Virology, November 2004, p. 12355-12365, Vol. 78, No. 22
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.22.12355-12365.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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