Open AccessProlonged and effective blockade of tumor necrosis factor activity through adenovirus-mediated gene transfer.
Author(s) -
Jay K. Kolls,
Karsten Peppel,
M. Silva,
Bruce Beutler
Publication year - 1994
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.91.1.215
Subject(s) - lymphotoxin , tumor necrosis factor alpha , adenoviridae , genetic enhancement , biology , lymphotoxin alpha , tnf inhibitor , in vivo , viral vector , recombinant dna , virus , viral replication , blockade , virology , microbiology and biotechnology , gene , receptor , immunology , etanercept , biochemistry
A chimeric protein capable of binding and neutralizing tumor necrosis factor (TNF) and lymphotoxin was expressed in mice transduced with a replication-incompetent adenoviral vector into which a TNF inhibitor gene had been engineered. Within 3 days following the injection of 10(9) infectious particles, the TNF inhibitor concentration exceeded 1 mg/ml of plasma; this level of expression was maintained for at least 4 weeks, and detectable TNF inhibitory activity was measured 6 weeks after injection of the recombinant virus. Introduction of the artificial gene produced a phenotypic effect comparable to homozygous deletion of the 55-kDa TNF receptor, in that animals were rendered highly susceptible to infection by Listeria monocytogenes, whereas control animals receiving a replication-incompetent virus coding for beta-galactosidase were capable of resisting Listeria challenge. Adenovirus-mediated transfer of a gene encoding a TNF inhibitor offers a practical means of imposing effective, long-term blockade of TNF activity in vivo for investigational and therapeutic purposes.