Replication-deficient adenoviruses

A replication-deficient adenovirus has been used to deliver a gene construct, which contains within its promoter region a radiation-responsive element. Upon irradiation with conventional doses of X rays, this construct initiates transcription of the gene coding for the toxic cytokine, tumor necrosis factor-a (35). The above is an exquisite example of how emerging delivery and gene therapies are fast blurring the distinction between an active and an excipient (Fig. 3D). 

Zsengeller ZK, Wert SE, Hull WM, Hu X, Yei S, Trapnell BC, Whitsett JA et al. Persistence of replication-deficient adenovirus-mediated gene transfer in lungs of immune-deficient (nu/nu) mice. Hum Gene Ther 1995 6(4) 457-467. 

Lemarchand, P., Jones, M., Yamada, I. and Crystal, R. G. (1993). In vivo gene-transfer and expression in normal, uninjured blood-vessels using replication deficient recombinant adenovirus vectors. Clin. Res. 41(2), A202. 

MuhlhauserJ, Jones M, Yamada I, et al, Safety and efficacy of in vivo gene transfer into the porcine heart with replication-deficient, recombinant adenovirus vectors, Gene Ther 1996 3(2) 145-1 53. 

Wiknott, R.W. and Whitsett, J., A phase 1 study of gene therapy of cystic fibrosis utilizing a replication deficient recombinant adenovirus vector to deliver the human cystic fibrosis trans-membrane conductance regulator cDNA to the airways. Bethesda, MD, Office of Recombinant DNA Activity, NIH. 

The ongoing clinical trials include the use of adenovirus and herpes virus vectors. One example of adenoviral vector is ONYX-015, which lacks E1B protein, required for replication with a normal p53 pathway and RNA export during viral replication. It has been used to treat squamous cell carcinoma of the head and neck and has also been tested as a preventive treatment for oral precancerous tissue. The concept behind using this vector is that ONYX-015 will proliferate in p53 pathway-deficient tumor cells and kill them. 

J. R. Bischoff, D. H. Kirn, A. Williams, C. Heise, S. Horn, M. Muna, L. Ng, J. A. Nye, J. A. Sampson, A. Fattaey, and F. McCormick, An adenovirus mutant that replicates selectively in p53-deficient human tumor cells, Science 274 313 (1996). 

Selective destruction of p53-deficient cells can be accomplished by genetically engineered adenovirus strains unable to replicate in cells with normal p53 (Bischoff et al., 1996). 

Bischoff JR, KimDH, Williams A, etal. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996 274 373-376. 

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