Research to unleash gene therapy on arthritis

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Research to unleash gene therapy on arthritis

Harvard team has volunteers ready

By Alice Dembner, Globe Staff | August 14, 2006

Within months, scientists will begin testing the first gene therapies

for osteoarthritis, in search of a more effective treatment and

perhaps a cure for the joint disease that afflicts more than 21

million Americans.

One effort, led by a Harvard Medical School researcher, is focusing

on a simple idea: Inject into the diseased joint a gene that will

continuously pump medicine right where it is needed. Another

project , led by a land company, will instead use genetically

modified cells to prompt growth of damaged cartilage.

Some of the work will piggyback on gene therapy experiments in

rheumatoid arthritis that are showing hints of effectiveness.

The arthritis studies are part of an expansion of gene therapy

research to diseases that are neither purely genetic nor necessarily

lethal. Seven years after the death of a healthy teenager in a flawed

experiment stalled most gene therapy studies, research is booming in

diseases ranging from Alzheimer's and angina to cancer and multiple

sclerosis.

In osteoarthritis, one ``goal is to convert the joint into a factory

that makes its own medicine, " said , a Harvard

professor of orthopedic surgery who is leading some of the new research.

The National Institute of Arthritis and Musculoskeletal and Skin

Diseases recently awarded a $1.6 million grant for the initial

tests of his treatment in people with moderately advanced arthritis.

Gayle Lester, who oversees clinical research in osteoarthritis for

the institute, calls the work ``a very strong and a very rational

approach to the disease. "

New treatments for osteoarthritis are desperately needed, especially

since the popular -2 painkillers Vioxx and Bextra were pulled from

the market nearly two years ago. None of the current options --

steroids, lubricants, pain pills, or dietary supplements -- alter the

course of the disease, and some do little to ease the pain and

disability. As cartilage in their joints erodes from injury and other

unknown causes, nearly 500,000 Americans every year face joint

replacement surgery, the Arthritis Foundation said.

``Gene therapy is one of the more promising areas for future

therapies for arthritis, " said Dr. Klippel, president of the

foundation.

plans to inject into the knee joint a virus whose genes have

been replaced by a human gene. The virus, which commonly infects

humans but causes no disease, will carry the gene inside the cells

that line the joint. There, the gene is expected to produce a steady

stream of a protein called interleukin-1-receptor antagonist to block

the inflammation and destruction of cartilage caused by another

protein, interleukin-1.

The therapy will be tried initially in nine volunteers who have

osteoarthritis that is bad enough to hamper their quality of life but

not to require joint replacement. hopes to begin the testing

within a year.

In dogs and rabbits, the technique preserved cartilage, and in

horses, it reduced lameness, said , who has patents on the

technology. The animals showed no harmful side effects.

``The animal data are fairly convincing in stopping the progression

of disease, " Lester said. And in Germany, tests of a drug made of the

same protein used in 's gene therapy have reduced arthritis

symptoms. However, the effects of the drug, Orthokine, now available

in Europe, wear off after a few months, he said. hopes the gene

therapy will provide more sustained relief.

At least three other groups of researchers worldwide are working on

gene therapy treatments for osteoarthritis, including teams in Japan,

Montreal, and at a land biotechnology company, TissueGene, that

has licensed 's patents and hired him as a paid consultant.

TissueGene is preparing to test a different technique, perhaps as

soon as this fall, in patients scheduled for total knee replacements

in Baltimore, according to J. Ganjei, vice president of

business development. Instead of injecting genes into the joint,

researchers plan to inject cells that have been genetically modified

to pump proteins that stimulate cartilage growth. After four weeks,

the patients will undergo knee replacement surgery, and the company

will collect the old joints for study.

Even if the first tests show the treatment is safe and offer some

hints of effectiveness, it could be a decade before any gene therapy

treatment for osteoarthritis is widely available.

All gene therapy research is proceeding cautiously because of

continuing public concerns about safety.

The death of 18-year-old Gelsinger in 1999 was followed three

years later by evidence that the first major gene therapy success --

treatment for a rare immune disorder known as ``bubble boy syndrome "

-- caused cancer. Since then, there has been steady progress toward

new treatments for immune disorders, cancers, and blindness, although

there is still no gene therapy product on the market in the United

States.

``We're more sober and more careful, " said Dr. Theodore Friedmann,

president of the American Society of Gene Therapy. ``The field has

become a bit more realistic about timeliness and about not promising

more than we can deliver. "

Lester said is working with materials that have a long history

of safe use and that a safety panel will monitor all aspects of the

experiment. But acknowledged that one serious side effect could

derail the effort.

Gelsinger, 's father, warns potential volunteers to get

involved in gene therapy studies only after asking lots of questions

about safety. ``If it's not life-threatening, I would go for much

more conventional treatment, " he said.

Carlene Lauffer, however, said she would volunteer in a minute,

although her arthritis is too advanced to qualify for 's

research. Lauffer, 78, suffers from osteoarthritis and rheumatoid

arthritis and has had finger joint replacements and a hip

replacement. She takes medicine for rheumatoid arthritis, an auto-

immune disorder in which the joint lining swells and produces a

substance that destroys the joint's surface. She also takes pain

pills for her osteoarthritis.

``I think there's a need for gene therapy " for arthritis, said

Lauffer, of Weirton, W.Va. ``We can maybe lick this. "

In 1996, Lauffer was the first patient to undergo gene therapy for

rheumatoid arthritis in an experiment run by and colleagues,

then at the University of Pittsburgh, that was designed to test only

the principle and safety. The researchers injected her knuckles with

the gene therapy or a placebo, monitored it for a week, and then

removed and replaced the diseased joints. In Lauffer and eight other

volunteers, they found that the gene entered cells in the joint and

pumped the same medicinal protein now being used in the

osteoarthritis research. Five years later, none of the volunteers had

any ill effects.

For rheumatoid arthritis, which affects more than 2 million

Americans, and at least four other groups of scientists are

pursuing clinical trials in gene therapy. Targeted Genetics, a

Seattle company, is furthest along, with preliminary results that

show a 20 to 30 percent reduction in swelling and tenderness in some

patients, said Pervin Anklesaria, vice president of therapeutic

development. The results have not yet been published.

Work on gene therapy for arthritis began with rheumatoid arthritis,

because scientists understand more about the underlying causes and

mechanisms, making targets for gene therapy more obvious. In

addition, the advance of the disease is fairly predictable, making it

easier to determine if new treatments are working.

Both the causes and biology of osteoarthritis remain mostly a

mystery, said, and the symptoms wax and wane, making testing of

treatments more difficult.

``Having a treatment that could be administered in the joint and stop

the progression or reverse the disease process would be very

attractive, " said Lester. ``That's what I find appealing about gene

therapy. "