Big Advance in Genetic Treatments Reported : Medicine: Researchers say new technique could allow doctors to fight diseases such as muscular dystrophy simply by injecting material directly into muscle tissue.
Researchers have developed a revolutionary way to treat genetic diseases that could greatly accelerate human gene therapy, which has been delayed for a decade by ethical considerations and technical problems.
Special genetic material would simply be injected into muscle tissue every few days or weeks in much the same fashion that insulin is now injected daily to treat diabetes.
The technique, developed by San Diego and Wisconsin scientists, could apply to a wide range of genetic diseases for which there is now no adequate therapy, ranging from muscular dystrophy to rare diseases of the immune system.
It might also serve as a way to deliver genetic engineering products, such as human growth hormone, much more cheaply than is currently possible.
In addition, according to researchers, it could be a valuable tool in the search for an AIDS vaccine or to help fight infections by the AIDS virus.
Conventional gene therapy involves using genetic-engineering techniques to replace a defective gene that causes illness with a healthy one. Geneticists have not yet received approval from regulatory agencies to attempt such therapy in humans.
Until now, scientists have experimented with replacing defective genes by using special viruses to insert healthy genetic material into an individual’s own DNA. But researchers and critics have feared that the viruses would insert the genes at the wrong site in DNA, thereby disrupting healthy genes.
In the surprisingly simple new technique, the researchers would simply inject specially prepared genetic material into the person’s muscle tissue, stimulating production of an enzyme or protein whose absence is the cause of the disease. The protein would be carried by the bloodstream to body tissues where it is needed.
Because a virus is not used, the injected material would pose no risk to the recipient’s genes.
The added genetic material would break down in a period of days to weeks, so the genetic therapy would be reversible if adverse effects should appear.
The researchers, from Vical Inc. in San Diego and the University of Wisconsin Medical Center in Madison, report in today’s Science magazine that they have used the technique successfully to produce proteins in mice. They hope to extend the studies to humans within five years, most likely for the treatment of muscular dystrophy.
“We are ushering in a very major change . . . that is going to push gene therapy ahead much faster in the next decade,” said biochemist Philip L. Felgner of Vical.
Although the researchers were looking for a way to introduce genetic information into cells, their discovery was serendipitous.
Felgner and his colleagues were working with messenger ribonucleic acid (mRNA), which serves as a sort of working copy of the genetic information contained in DNA (deoxyribonucleic acid) that is used by the cell’s protein-making machinery.
The mRNA has certain potential therapeutic applications in its own right, and many laboratories are looking for ways to get it inside cells. Vical has been working with liposomes, microscopic globules of fat that would encase the mRNA and carry it into cells. To test how well the liposomes worked, researchers decided to inject naked mRNA into tissues, assuming that none of it would make it into cells.
They were wrong.
The naked mRNA was taken up by the cells faster than the mRNA in liposomes. “I didn’t believe it at first,” said medical geneticist Jon A. Wolff of Wisconsin. “It was a total surprise,” Felgner added. “Nobody would have even thought to (try it).”
After they convinced themselves that the mRNA was being taken up, research progressed rapidly. “The procedure is extremely simple,” Felgner said. “It’s simple to administer the mRNA, and it’s simple to make it. It’s straightforward molecular biology.”
They do have to modify the mRNA, though. Special segments of RNA must be added to the ends of the RNA gene for the cells to make proteins from it. Additional segments must be added if the cells are to secrete the proteins into the bloodstream.
The mRNA is broken down and absorbed by the cells within two or three days, so continuous replacement is necessary. But Felgner and Wolff have been able to circumvent that problem by modifying the genetic information so that it persists for as long as six months.
One of the most promising uses of the technique might be for treating muscular dystrophy, which causes progressive weakening and wasting of muscles. About one in every 3,500 males develops the disease.
Researchers discovered two years ago that the muscle cells of muscular dystrophy victims lack a specific protein, called dystrophin, that is necessary for muscle function. Felgner speculates that the new technique could readily be used to have muscle cells produce the protein right where it is needed. He is now preparing experiments in which the dystrophin gene will be injected into dystrophic mice, and hopes to have them completed by the end of the year.
The technique theoretically could also be used to treat any genetic disease requiring that a protein or enzyme be released into the blood. In one type of rare immunodeficiency disease that genetic engineers are contemplating treating, for example, the victims are missing a crucial enzyme called adenosine deaminase.
Felgner speculates that such a condition could be treated easily with the new technique, so that muscle cells would secrete the missing enzyme.
Other missing hormones and biological agents that now must be injected on a regular basis, such as human growth hormone, could be produced in the same fashion. Because injections of a plasmid would be required only every six months or so, rather than daily or several times a week, the cost would be greatly reduced.
The technique probably could not be used for treating diabetes, however, because the production of insulin must be much more closely regulated than is possible in muscle cells.
Finally, the technique could be used to produce vaccines against the AIDS virus and others. If muscle cells could be induced to produce certain AIDS proteins, speculated immunologist Howard Gray of Cytel Corp. in San Diego, a much more effective immune response would be produced against the virus.
