Gene therapy eases
multiple sclerosis in mice
BY RUTHANN RICHTER
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 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, professor 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.
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 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.
Dr. Richard dal Canto, a
graduate student in Fathman's laboratory, presented the
results of the mouse study April 19 at the annual meeting
of the Federation of American Societies for Experimental
Biology, held in San Francisco. The other scientists
involved in the work were Michael K. Shaw, a postdoctoral
fellow in Fathman's lab; Dr. Lawrence Steinman, professor
of neurology and neurological sciences; and Garry Nolan,
assistant professor of molecular pharmacology.
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. 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.
He 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.
"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," Fathman
said.
To do that, the
researchers used specially tailored retroviruses devised
by Nolan. 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," dal Canto 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."
He 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.
"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.
Funding for the study came
from the National Institute of Allergy and Infectious
Disease. SR
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