Using a unique combination of innovative technologies, scientists have demonstrated the ability to introduce therapeutic genes into the body and then, further, to precisely control the activity of those genes with a drug that could be given as a simple pill.
The novel gene therapy system, developed by researchers at the University of Pennsylvania Medical Center and ARIAD Pharmaceuticals in Cambridge, MA, represents an entirely new form of drug delivery, one that opens the door to many therapies not previously possible. A report on the experimental study, performed in mice and monkeys, will appear in the January 1, 1999, issue of Science. (Copies of the final version of the paper are available to reporters through the journal's news office at 202-326-6421.)
"We're excited about these results, because they create many new opportunities for experimental and then clinical applications of gene therapy that we couldn't consider before," says James M. Wilson, MD, PhD, director of the Institute for Human Gene Therapy at Penn and senior author on the report. "This system will allow us to modulate the expression of a delivered gene in response to changes in a patient's disease."
The new system couples advances at Penn allowing the long-term introduction of genes into the body with a patented technology (ARGENT) to regulate gene activity from ARIAD.
As the culmination of several years of concerted effort, Penn researchers recently succeeded in optimizing a gene therapy viral vector to achieve long-term protein production without sparking an immune-system reaction. The vector is an engineered version of a virus known as adeno-associated virus, or AAV, which is a very small, innocuous virus.
For this project, the Penn and ARIAD scientists stripped two AAVs of their viral genes and reloaded them respectively with the gene for erythropoietin, or Epo, a recombinant protein that stimulates red blood cell production and is used to treat anemias, and the genes for a transcription factor complex able to regulate Epo.
ARIAD investigators had previously shown that this particular transcription factor could be switched on by a small-molecule drug called rapamycin, which can be taken orally. Significantly, the amount of rapamycin administered controlled the level of Epo produced by cells exposed to the AAV vectors.
"It's a very precise gene switch, a kind of molecular rheostat," explains Wilson. A common example of a rheostat is the so-called dimmer switch used with some household lights.
In mice and in rhesus monkeys, giving more rapamycin stimulated a proportionate rise in production of Epo, resulting in higher numbers of red blood cells in the bloodstream. Conversely, stopping administration of rapamycin shut down production of Epo. The effects of the treatment were tracked for six months in mice and three months in monkeys.
Epo was chosen as a demonstration gene for the new drug delivery system because it is a therapeutically significant drug that currently must be given by injection several times a week and because its action can easily be measured through red blood cell counts.
"The ability to achieve dosage control of a drug in the context of gene therapy is going to be critical to making a number of new treatments possible," says Michael Gilman, PhD, chief scientific officer at ARIAD and a coauthor on the Science study. "Many of the proteins we would like to produce in the body using gene therapy are quite potent and can have side effects, so being able to carefully adjust their levels within a therapeutic window is going to be key."
The new method has some distinct advantages over current drug delivery systems, Gilman adds. With oral or injectable drugs, the patient experiences peaks and valleys in the amount of drug in the blood, which rises sharply after administration and then declines steadily until the next dose. Side effects are often most severe during peaks and then drop to levels that may not provide therapeutic benefit during valleys.
"One of the real advantages of using gene therapy to deliver drugs is that you can deliver them in a steady trickle that can be adjusted through administration of a pill," says Gilman.
Further development of this technology aiming at eventual clinical trials is currently under way. A joint venture exists between ARIAD and Genovo Inc., Philadelphia, PA, a biotechnology company founded by Wilson and in which he holds equity.
Xuehai Ye, PhD, at Penn is lead author on the paper. Other Penn-based coauthors include Philip Zoltick, MD; Michael A. Schnell, DVM; Guang-ping Gao, PhD; and Joseph V. Hughes, PhD. ARIAD-affiliated coauthors are Victor M. Rivera, PhD; and Franklin Cerasoli Jr., PhD. Support for the study was provided by the National Institutes of Health, ARIAD Pharmaceuticals, and Genovo Inc.
The University of Pennsylvania Medical Center's sponsored research and training ranks third in the United States based on grant support from the National Institutes of Health, the primary funder of biomedical research and training in the nation -- $175 million in federal fiscal year 1997. In addition, for the third consecutive year, the institution posted the highest annual growth in these areas -- 17.6 percent -- of the top ten U.S. academic medical centers. News releases from the University of Pennsylvania Medical Center are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the medical center's home page (http://www.med.upenn.edu), to EurekAlert! (http://www.eurekalert.org), an Internet resource sponsored by the American Association for the Advancement of Science, and to the electronic news services Newswise (http://www.newswise.com).
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Science