4/16/98
CONTACT: Ruthann Richter or Kent Safford, (650) 723-6911; Dr. C. Garrison Fathman, (650) 723-7887
EMBARGOED FOR RELEASE at 10 a.m. U.S. Pacific Daylight Time on Sunday, April 19, to correspond with presentation at the annual meeting of the Federation of American Societies for Experimental Biology, held at San Francisco's Moscone Center. The meeting press room number is (415) 978- 3509.
MEDIA AVAILABILITY: Drs. Fathman and Richard dal Canto will be available to answer reporters' questions at noon Sunday, April 19, in the press room (room 232) of the Moscone Center in San Francisco.
GENE THERAPY EASES MULTIPLE SCLEROSIS IN MICE
STANFORD - A gene therapy technique that sends inflammation- squelching proteins directly where they're needed can help allay the symptoms of a disease resembling multiple sclerosis (MS) in mice, Stanford scientists have found.
Using specially inactivated retroviruses as a delivery vehicle, the researchers were able to insert a gene coding for anti-inflammatory proteins, known as suppressor cytokines, into immune system cells that naturally home in on inflamed tissues.
The immune cells then began churning out the inflammation-fighting proteins where they were most needed, said the study's principal investigator, Dr. C. Garrison Fathman, a professor of medicine (immunology and rheumatology) at Stanford University School of Medicine.
Mice treated with the tailored viruses showed less severe symptoms of the MS-like disease than untreated mice, Fathman said.
"We can give a very limited amount of the [cytokines] in a highly defined area so that we only target areas of inflammation where the tissue is being destroyed," he said.
Potential for arthritis, diabetes
Although his group's latest experiments tested the technique in mice with MS, Fathman said the same approach could apply to rheumatoid arthritis and diabetes, which involve a similar inflammatory process.
The Stanford researchers now are looking at ways to adapt the technique for use in humans.
"We are very seriously considering the appropriate strategy to address MS or rheumatoid arthritis in which we could adapt this therapy in the not-too- distant future for human clinical trials," Fathman said. Those trials would not begin for at least another year, he added.
The results of the mouse study were scheduled to be presented Sunday, April 19, by Dr. Richard dal Canto, a graduate student in Fathman's laboratory, at the annual meeting of the Federation of American Societies for Experimental Biology, held in San Francisco.
The study focused on mice with a disease known as experimental autoimmune encephalomyelitis, which serves as an animal model for MS. In both diseases, the immune system turns against the very tissues it was designed to protect, attacking a protein called myelin that insulates nerves. The nerve impulses then go awry, causing impaired vision and motor control and leading to a gradual decline in function that ends in death.
This disease process depends on the action of cytokines, hormone-like substances released by the immune system's T-helper cells.
Putting out brushfires
Some cytokines suppress inflammation, while others promote it. The inflammatory cytokines can spark little "brushfires" in the body, Fathman said. This is the inflammation that leads to the pain of rheumatoid arthritis or the functional loss that comes with MS.
"The presumption is that if we could put out the brushfires with the suppressor cytokines, we could achieve homeostasis and put the immune system back into a state where it can fend off disease, not fight [the body] itself," he said.
Fathman and his colleagues reasoned that if they could find a way to insert the gene for the suppressor cytokines into T-helper cells - which naturally gravitate to inflammation sites - the cells would spill out the fire-dousing molecules where they were most needed.
Special delivery
To do that, the researchers used specially tailored retroviruses devised by Garry Nolan, a Stanford assistant professor of molecular pharmacology and of microbiology and immunology. Nolan and his colleagues were able to repackage these retroviruses to carry the gene for the suppressor cytokines while disabling the viruses so that they could not reproduce once they were inside the cell.
The use of retroviruses, said dal Canto, helps solve a major challenge in gene therapy: how to get the gene where it's needed and get it to stay there long enough.
"Retroviruses permanently integrate themselves into the DNA, so they make ideal vehicles," he said. "So this is a way of permanently putting the DNA into the cell and getting the cytokine we need to the right part of the body while taking advantage of the homing properties of these immune cells."
Dal Canto noted that most treatments for autoimmune diseases, including rheumatoid arthritis and MS, take a global approach, suppressing the immune system generally. But that approach can be dangerous because it leaves the body open to infection, he said.
"This [new] method is a way to target the molecule to the site of injury, thereby avoiding the toxicities involved in more systemic approaches," dal Canto said.
The researchers were able to monitor the amount of suppressor cytokine being produced by tagging the inserted gene with a green fluorescent "marker." If the T-helper cells were bright green, that meant they were producing lots of the helpful protein. Knowing this enabled the researchers to calibrate the dosage levels and minimize toxicity, Fathman said.
The other scientists involved in the work were Michael K. Shaw, a postdoctoral fellow in Fathman's lab, and Dr. Lawrence Steinman, professor of neurology and neurological sciences.
Funding for the study came from the National Institutes of Health.
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