Defending the Joints

By Kathy A. Svitil|Saturday, October 01, 1994
RELATED TAGS: GENES & HEALTH
Gene therapists are trying to correct one of the immune system’s mistakes: the vicious civil war called rheumatoid arthritis.

Rheumatoid arthritis won’t kill you. Nevertheless, it’s a terrible disease: the body, for reasons not understood, commits a devastating betrayal, launching an all-out attack against the joints. They become swollen and inflamed; eventually the cartilage that cushions them is completely destroyed, leaving bone grinding on bone, and a patient in excruciating pain. That’s why rheumatoid arthritis has become the first nonlethal disease on which gene therapy is being attempted. The first human clinical trials are scheduled to start this winter, led by researchers at the University of Pittsburgh School of Medicine. The trials will only be preliminary, designed to test the treatment’s safety and feasibility. But to the more than 2 million Americans who suffer from the debilitating disease, the promise of a new therapy, however far off it might be, is encouraging news.

Joints consist of bone, cartilage, synovial tissue, and a fluid- filled cavity. In the knee, for example, strong, elastic cartilage caps the ends of the femur and the tibia; the cartilage is covered by a thin membrane of cells called the synovial lining. The synovial lining secretes a fluid that oils the joint, keeping it moving smoothly. At least, that is the situation in normal, healthy joints. In joints where rheumatoid arthritis rages, however, something has gone terribly wrong.

What usually happens in rheumatoid arthritis is that you get an immune reaction against something in the joint, says molecular geneticist Paul Robbins, one of the leaders of the Pittsburgh team. It’s an autoimmune disease, where the body mistakes something, like the collagen of the knee, for a foreign invader and responds.

That response is swift and severe. Huge volumes of blood cells flood the joint cavity, making it swell. The synovial cells begin reproducing at a rapid pace, forming benign, tumorlike growths in the joint; cartilage begins to break down, and the synthesis of new cartilage is shut off, preventing its repair. As the cartilage is lost, Robbins says, you eventually get to the point where you have bone rubbing on bone. And at that point you have no choice for patients except joint replacement- -putting in an artificial joint--or joint fusion. Fusing two bones eliminates the pain of rheumatoid arthritis, but also the flexibility that a joint provides.

Exactly what causes the symptoms of rheumatoid arthritis is not known. But nearly all of them seem to be associated with an excess in the joints of cytokines--immune-system messenger molecules--and in particular of a cytokine called interleukin-1. Robbins and his colleague, biologist Chris Evans, decided that the best way to stall the onslaught of the disease would be to block interleukin-1 in the affected joints. And the best way to do that, they figured, was by using the same chemical the body normally uses for the job: interleukin-1 receptor antagonist protein, or IRAP. IRAP binds to the same receptor molecules that allow interleukin-1 into cells. When all those receptors are flooded with IRAP, interleukin-1 can’t get into cells and can’t deliver its traitorous message.

Synovial cells in the joints of arthritis patients already produce IRAP--but not enough, Robbins and Evans thought, to rein in the excess interleukin. That is why adding IRAP may help. Indeed, other researchers have injected IRAP into joints and have had success at reducing the symptoms of the disease. But they were not really that successful, says Robbins, since the patients needed daily injections. Daily injection into an inflamed joint is not a procedure people tolerate.

A better way to get lots of IRAP into joints, Robbins and Evans thought, was to get lots of the IRAP gene into joints. With extra copies of the gene, the patient’s cells would make more IRAP on their own. That’s what Robbins and Evans will be trying to achieve with six human patients who suffer from advanced rheumatoid arthritis.

The patients who will be selected will each need two operations: one for knuckle joint replacements and, before that, some other joint surgery, such as a wrist fusion. In the first round of surgery, synovial cells will be removed from the patients’ joints and given to Robbins and Evans. The researchers will expose the cells to a harmless retrovirus into which they have engineered the IRAP gene. The idea is that the retroviruses will then insert their own genetic material into the DNA of the synovial cells--that’s how retroviruses operate--along with the stowaway IRAP gene. If all goes as planned, the synovial cells will then start producing more IRAP.

One week before their knuckle replacements, the six patients will have their own synovial cells injected into their knuckle joints. Some joints in each patient will get cells with the IRAP gene; others will get unaltered cells, as a control. And then, a week later, when the knuckles are taken out and the artificial joints put in, says Robbins, our labs will get back the synovial cell samples, as well as cartilage and everything else in the joint.

Robbins and Evans will analyze those samples, hoping to find evidence of IRAP-induced changes. They know what to look for: in similar experiments on rabbits, IRAP reversed nearly all the symptoms of the disease for six to seven weeks. (For some reason, the injected cells either died or stopped producing IRAP after that.) The volume of blood cells infiltrating the joints was cut in half; the growth of synovial cells slowed dramatically; the cartilage stopped disintegrating and even started to repair itself again. Moreover, the process seemed to be self-regulating: though it’s not known why, the injected synovial cells produced the most IRAP in the joints that needed it most, the ones that were particularly inflamed.

Robbins and Evans aren’t expecting to see that dramatic an improvement in their human patients after only one week of IRAP gene therapy. Indeed, the first round of patients won’t benefit from the treatment at all, since their knuckles were in such poor condition that they needed to be replaced anyway. The patients in the trial will just be paving the way for the many thousands of others whose rheumatoid arthritis is at an earlier stage, and who could still benefit from an effective gene therapy.

What we are hoping is that, at the very least, we can get the cells back in and get the protein expressed at some biologically active level, says Robbins. If that happens, and if the patients have no side effects, that, for us, would be a successful trial.
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