By designing a special gene that can be turned on and off as needed, and then making it work in live animals, researchers in Pennsylvania said this week that they have taken a vital step toward gene therapy.
Scientists at the University of Pennsylvania School of Medicine have tailored a genetic system so that it can be controlled from outside the animal by giving doses of a drug, rapamycin, according to Dr. James Wilson and his colleagues.
The three-part system has been shown to work in mice and monkeys, and has continued working for months. This suggests that it will probably work in humans with serious genetic diseases.
"This is an important step toward controlled gene therapy," Wilson said in an interview Thursday. "We think it will expand the scope of gene therapy, and make it safer, because we have a way to turn it off."
Dr. W. French Anderson, who has pioneered the research on gene therapy, said Wilson's report in the journal Science yesterday "is very exciting. It's very nice work. It's the first I'm aware of with in vivo regulated gene expression."
In other words, it's the first time that an extra gene has been inserted into healthy live animals that is fully controllable, its activity capable of being turned up, down, on and off.
Treating human diseases
Anderson, of the University of Southern California Medical School in Los Angeles, said the fact that Wilson's system has been made to work, and has kept working, in monkeys "is very significant, because it means it should work clinically" -- in human patients.
The goal of such research is to find ways to defeat a number of inherited diseases that have essentially been unapproachable. Inherited maladies such as sickle-cell anemia, hemophilia and Lesch-Nyhan syndrome have resisted treatments and cures because they are caused by gene mutations -- genetic errors -- that cannot yet be corrected. As a rule, such inherited diseases cannot even be treated.
A few genetic diseases, such as PKU (phenylketonuria), can be ameliorated by manipulating a child's diet to avoid severe mental retardation. Hemophilia can be partially controlled by injections of blood-clotting factors. And some inborn ailments can be cured by drastic measures such as bone-marrow transplants or liver transplants.
Two genes and two viruses
In the encouraging new experiments, Wilson and his colleagues used two kinds of genes. One makes the protein they want to supply to the body, erythropoietin (EPO), and the other gene is needed to activate the first gene. The genes are engineered into separate viruses, which are then mixed together and injected into the animals' muscles.
After the viruses have been injected, and the genes have gone into muscle cells, however, the system remains dormant until the animal is given the drug rapamycin. The drug causes the two genes to work together so that they begin making the protein, EPO. If the researchers stop supplying the drug, the gene system stops working.
Their new gene control system works so well, Wilson said, that the amount of EPO being made can be precisely controlled by the amount of rapamycin given. EPO is a hormone-like factor that stimulates production of red blood cells. It is already a commercial product used to treat anemia.
Rapamycin is already a marketed drug, used mainly for immune suppression. But the doses used in the animal experiments are so low that normal immune function is not affected, Wilson said.
"When we gave rapamycin, it induced the gene and did everything we wanted it to do," Wilson said. When they stopped giving rapamycin, the gene stopped making EPO. "And when we gave more of the drug, it expressed more of the protein," Wilson said.
The virus vehicles used to carry the genes into muscle cells are engineered versions of the benign AAV -- adeno-associated virus -- which causes no human diseases, Wilson said.
Numerous other research teams, including Anderson in California, are working to tailor AAV for similar gene therapy experiments.
Pub Date: 1/02/99