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Y.P. Yang, F.A. Nunes, K. Berencsi, E. Gonczol, J.F. Engelhardt, J.M. Wilson, "Inactivation of E2a in recombinant adenoviruses improves the prospect for gene therapy in cystic fibrosis," Nature Genetics, 7:362-9, 1994. (Cited in more than 75 publications as of April 1996) Comments by James M. Wilson, University of Pennsylvania VIRUS BASHER: Penn's James Wilson limits the mouse immune reaction when testing gene therapy for cystic firbrosis. His technique: Cripple the viral vector. The first human trial that used a virus to transport a cystic fibrosis gene (R.G. Crystal et al., Nature Genetics, 8:42-51, 1994; Hot Papers, The Scientist, Feb. 19, 1996, page 13) was conducted in 1994. Researchers engineered an adenovirus to carry the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is missing in sufferers of the disease. However, about a week after therapy was given and the gene-carrying virus delivered its load, the body's immune system reacted. The resulting inflammation caused the new gene's effects to be short-lived. In this paper, James M. Wilson, director of the Institute for Human Gene Therapy at the University of Pennsylvania, describes findings that demonstrate how the immune system limits the effectiveness of the therapy as originally conceived. He further shows that the best way to circumvent such problems may be to partially cripple the adenovirus. His research team's experiments showed that such viruses would likely attract less attention from the immune system and perhaps allow the gene's effects to last longer. In the Nature Genetics work, his group gave the gene-carrying virus to a normal mouse. "We saw good gene transfer, and the expression disappeared with inflammation," explains Wilson, who also is professor and chairman of the department of molecular and cellular engineering. "We repeated the experiment with a mouse that had a genetically deficient immune system. There was far less inflammation, and the gene expression was stable. "That was a turning point," he says. "It suggested that the immune response to the therapy might be an important barrier to using vectors in the treatment of chronic diseases. If we could somehow eliminate the immune response, then the vectors would be useful." Yet, Wilson notes, "there was another possible explanation why the vector would persist in an immune-deficient animal: The vector was capable of replicating and could continue to spread from one cell to another." To test that hypothesis, Wilson's team created a "second-generation" viral vector that lacked two types of genes, E1 and E2a. "If the reason the vector persisted in an immune-deficient animal was because the vector replicates and spreads, and you make it more defective, it will be less stable in an immune-deficient animal," he states. Yet a subsequent experiment showed the vector was stable. This demonstrated that the defective virus could still deliver genes and was stable in an immune-deficient animal. "That opened the concept of making the vectors more defective-and less reactive with the immune system-as something to try to make the technology better," he recalls. "We terminated our clinical trial that was using just an E1-defective vector and went back into the laboratory and have spent two years trying to make a variety of more defective vectors, as have others in the field." Wilson's group reported similar immune responses in the mouse liver (Y. P. Yang et al., Proceedings of the National Academy of Sciences, 91:4407-11, 1994). Other scientists recently validated Wilson's animal findings using genetically modified cells in human gene therapy (S.R. Riddell et al., Nature Medicine, 2:216-23, 1996). Wilson calls his group's observations "a wake-up call that the immune response to the vector is really something that we have to understand." He hopes to design strategies for using drugs given with the vector to prevent an immune response.

Gene Therapy

The Scientist Staff

Jun 9, 1996

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