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Courtesy of ARIAD Pharmaceuticals In the gene therapy system devised by Penn and ARIAD researchers, the adeno-associated virus is injected into the body to deliver the desired gene (top left), and a drug in pill form is given orally to activate gene expression (top right). Researchers demonstrated a strong correlation between the amount of drug administered and the resulting increase in the amount of protein produced (center). Scientists attempting to devise successful, efficient gene therapy systems face three major challenges: transference, persistence, and regulation. First, they must deliver the desired gene into target cells and ensure that it remains in those cells for an extended period of time. They must then, in many cases, regulate that gene so that it's only active when needed. Two recent papers, one in the Jan. 1 issue of Science1 and another in the Jan. 19 issue of Proceedings of the National Academy of Sciences (PNAS),2 have reported advances in the construction of regulatory systems, the trickiest of the three challenges. In experiments that may one day improve the delivery and regulation of many types of pharmaceuticals, investigators have designed systems in which genes can be switched on and off when needed via the administration of some exogenous agent, such as a pill. Generally, gene therapy specialists avoid applications that require gene regulation; there simply hasn't been a reliable, feasible regulatory mechanism. "In the process, we've eliminated a substantial number of potential targets and candidates," says James Wilson, director of the University of Pennsylvania's Institute for Human Gene Therapy and senior author of the Science paper, a collaborative effort with ARIAD Pharmaceuticals of Cambridge, Mass. "We [made] this sort of design from the ground up...[it] really was tuned to work in the clinic," explains Michael Gilman, chief scientific officer at ARIAD and a coauthor of the Science study. Penn and ARIAD researchers first stripped two adeno-associated viruses (AAVs) of their viral genes. They reloaded one with the gene for erythropoietin (Epo), a recombinant protein that stimulates red blood cell production and is used to treat anemias. They armed the other with the genes for a transcription factor complex that regulates Epo and is itself known to be regulated by a small-molecule drug called rapamycin that can be taken orally. Mice and rhesus monkeys injected with the virus demonstrated a rise in Epo production--and consequently an increased number of red blood cells--proportionate to the amount of rapamycin given. Researchers chose Epo because it has proven therapeutic value, and because its biological effects are easy to measure. "You could swap the gene for virtually anything, then secrete," remarks Wilson, who claims that his lab has achieved equally positive results using growth hormone and has started to test other cytokines. "It's a very cassette-oriented approach." "It worked basically the first time we did it," notes Gilman. "Finding the optimal configuration and ... working the kinks out took a little while, but [the result] wasn't really any great conceptual breakthrough." A similar system, devised in a study headed by scientists from Baylor College of Medicine in Houston, uses mifepristone, or RU486, in pill form to trigger the activity of a gene for human growth hormone in mice. Used in small doses to treat brain tumors, fibroids, and breast cancer, RU486--chosen primarily because it's readily available--is perhaps best known for inducing abortion when administered at doses 1,000 times greater. Along with the growth hormone gene introduced, investigators delivered a modified progesterone receptor that's only activated by antiprogestins such as RU486. "I would say these are the two best [regulatory systems] out there now," asserts Bert O'Malley, senior author of the PNAS study and chairman of cell biology at Baylor, referring to both his team's research and that of the Penn/ARIAD team. The two approaches differ in some respects, most notably with regard to the vectors employed. While the Penn/ARIAD group used AAV, which has come onto the scene only within the last couple of years, Baylor researchers chose to use an adenovirus vector, which, as with AAV, was stripped of viral genes. Though AAV appears to be more stable and less likely to be rejected by the immune system, adeno is cheaper and more readily available.3 While suggesting that both systems are viable, O'Malley cites a potential advantage of his system: The antiprogestins used in their study are already commonly taken by people at the necessary concentrations. Before the Penn/ARIAD group pursues clinical trials with its system, ARIAD scientists will take a rapamycin analog into a simple Phase I trial to prove that it is nontoxic. Penn researchers will take the vector alone, minus rapamycin, into the clinic to establish its safety. The Penn group plans, by no later than January 1, 2001, to unite the vector with the regulated system in a clinical trial targeting thalassemia, a severe inherited anemia. O'Malley's group plans to do more animal studies this year and hopes to begin clinical studies in humans by next year. He says of systems such as his: "It's just a continuing development in this new field of gene therapy, which, in the new millennium, is going to be a revolutionary thing in pharmaceuticals." X. Ye et al., "Regulated delivery of therapeutic proteins after in vivo somatic cell gene transfer," Science, 283:88-94, Jan. 1, 1999. M.M. Burcin et al., "Adenovirus-mediated regulable target gene expression in vivo," Proceedings of the National Academy of Sciences, 96:355-60, Jan. 19, 1999. P. Smaglik, "Gene Therapy--The Next Generation," The Scientist, 12[10]:4-5, May 11, 1998.

New Gene Therapy Systems: Advancement in Drug Delivery

Feb 1, 1999

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