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Journal of Virology, January 2004, p. 912-921, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.912-921.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

PEGylation of a Vesicular Stomatitis Virus G Pseudotyped Lentivirus Vector Prevents Inactivation in Serum

Maria A. Croyle,1,2* Shellie M. Callahan,1 Alberto Auricchio,3 Gregg Schumer,4 Klause D. Linse,2 James M. Wilson,4 Lane J. Brunner,1 and Gary P. Kobinger4

Division of Pharmaceutics, College of Pharmacy,1 Institute for Cellular and Molecular Biology, The University of Texas at Austin Austin, Texas 78712,2 Telethon Institute of Genetics and Medicine, Naples, Italy,3 Gene Therapy Program, Division of Medical Genetics, University of Pennsylvania, and the Wistar Institute, Philadelphia, Pennsylvania 191044

Received 2 May 2003/ Accepted 25 September 2003

One disadvantage of vesicular stomatitis virus G (VSV-G) pseudotyped lentivirus vectors for clinical application is inactivation of the vector by human serum complement. To prevent this, monomethoxypoly(ethylene) glycol was conjugated to a VSV-G-human immunodeficiency virus vector expressing Escherichia coli beta-galactosidase. The modification did not affect transduction efficiency in vitro and protected the vector from inactivation in complement-active human and mouse sera. Blood from mice dosed intravenously with either the unmodified or the PEGylated virus particles was assayed for active vector by a limiting-dilution assay to evaluate transduction efficiency and for p24, an indicator of the total number of virus particles present. PEGylation extended the circulation half-life of active vector by a factor of 5 and reduced the rate of vector inactivation in the serum by a factor of 1,000. Pharmacokinetic profiles for the total number of virus particles present in the circulation were unaffected by PEGylation. Modification of the vector with poly(ethylene) glycol significantly enhanced transduction efficiency in the bone marrow and in the spleen 14 days after systemic administration of the virus. These results, in concert with the pharmacokinetic profiles, indicate that PEGylation does protect the virus from inactivation in the serum and, as a result, improves the transduction efficiency of VSV-G pseudotyped lentivirus vectors in susceptible organs in vivo.

* Corresponding author. Mailing address: Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, PHR 4.214D, Austin, TX 78712. Phone: (512) 471-1972. Fax: (512) 471-7474. E-mail: macroyle{at}mail.utexas.edu.

Journal of Virology, January 2004, p. 912-921, Vol. 78, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.2.912-921.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.





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