Countering Crohn’s Disease

Research moves forward in clinical trials

Researchers at Washington University School of Medicine and several other centers around the United States soon will begin recruiting patients to further study a potential treatment for Crohn’s disease, a chronic and serious inflammatory disease of the gastrointestinal tract that affects about half a million people in the United States. The phase III trial recently was announced by Berlex Laboratories, Inc., the manufacturer of the drug that is being investigated.

Later this month, Joshua Korzenik, M.D., assistant professor of medicine at Washington University School of Medicine, will present preliminary data from the recently completed, multicenter trial at an American College of Gastroenterology meeting. That study began almost two years ago and followed 124 patients with moderate to severe Crohn’s disease at 33 centers around the United States.

Patients treated in the GM-CSF pilot study showed a decrease in inflammation: an inflamed colon before treatment (top) and after, showing no pathologic abnormality.
Patients treated in the GM-CSF pilot study showed a decrease in inflammation: an inflamed colon before treatment (top) and after, showing no pathologic abnormality.

Some received an inactive placebo. Others got daily injections of a drug called GM-CSF (granulocyte macrophage colony stimulating factor), which stimulates the activity of certain cells in the immune system. In the past, GM-CSF was used primarily in patients undergoing chemotherapy for leukemia.

Crohn’s disease always has been considered the result of an overactive immune system, so most therapies have attempted to suppress the body’s immune response. But the studies of GM-CSF have looked at whether revving up part of the immune system can relieve symptoms.

A typical Crohn’s patient regularly deals with diarrhea, abdominal pain and intra-abdominal infections. Frequently, the disease closes off sections of the intestine, and patients need surgery to eliminate blockages.

Korzenik works with Brian Dieckgraefe, M.D., Ph.D., also an assistant professor of medicine in the division of gastroenterology and staff physician at Barnes-Jewish Hospital.

“Brian is primarily in basic science,” Korzenik says. “I’m in clinical science, and our ideas grew out of discussions between us as we thought about how we might be able to help patients with Crohn’s disease, because so many don’t get relief from current treatments.”

Joshua Korzenik
Joshua Korzenik

Dieckgraefe started out working with gene chips, conducting studies to find genes turned on and off during Crohn’s disease. Initially, those studies weren’t much help because in patients with Crohn’s disease, the immune response is so revved up that many genes are activated.

So Dieckgraefe took a step backward, and the research effort began to concentrate on genetic events that might occur earlier in the disease cascade, before most symptoms appear.

Because Crohn’s disease was thought to result from an impaired immune response, they looked at other genetic diseases that also impair immunity.

“There are probably 20 different mutations that lead to impaired immunity,” Dieckgraefe explains. “They affect a part of the immune system called innate immunity, first-line cells that launch initial attacks on bacteria and other microbes.”

The researchers looked at two disorders in particular: glycogen storage disease 1B and a disorder called chronic granulomatous disease. Dieckgraefe reasoned that by learning how these genetic disorders shut down innate immunity, they might be able to mimic some of those genetic mutations and changes. In theory, that might make it possible to use gene therapy to impair immune response, thereby helping Crohn’s disease patients.

At least that’s how the project started. But the studies of patients with impaired immunity revealed some startling things.

“Much to our surprise, we found that in some of these immune disorders, patients develop a clinical illness that is indistinguishable from Crohn’s disease,” Dieckgraefe says. “These people had impaired immune systems, and they had Crohn’s disease, too.”

Brian Dieckgraefe

Brian Dieckgraefe

Was it possible, they wondered, that the conventional thinking on Crohn’s disease was incorrect? Maybe the immune system only became overactive as a way to compensate for a weak response earlier in the disease cascade. What would happen to Crohn’s disease symptoms if these patients with genetic immune diseases were treated with drugs that actually enhanced their innate immune response?

The answer to that question was already out there. Back in 1991, two drugs became routinely available in the United States to help correct impaired immunity in these patients. One of them was GM-CSF. The other was a similar drug called G-CSF (granulocyte colony stimulating factor). Both drugs used natural proteins to jump-start innate immunity and help patients live with their immune system disorders.

Dieckgraefe and Korzenik also learned that when those patients with rare immune system disorders took the drugs, their Crohn’s disease symptoms went away.

They decided it might be worthwhile to look at treating Crohn’s disease by stoking up the body’s innate immunity, rather than impairing it.

“At first blush, the idea of priming the immune system in patients with Crohn’s disease sounds sort of like throwing oil on a fire,” Korzenik says. “You might compare it to proposing a high cholesterol diet to treat heart disease.”

Oddly enough, it appears to work. A preliminary study published last fall in The Lancet reported that enhancing the body’s innate immunity can improve symptoms of Crohn’s disease in 80 percent of patients with moderate to severe forms of the debilitating, inflammatory gastrointestinal disorder. And although the data have not yet been presented, the results from the placebo-controlled phase II treatment study were positive.

Patients in the study took daily injections of GM-CSF, also known by the trade name Leukine® (sagramostim), and most got better. But maintenance trials showed that Crohn’s disease symptoms returned when patients stopped taking the drug.

Based on those preliminary results, Berlex Laboratories Inc. — the pharmaceutical firm that owns Leukine — initiated the large-scale, multicenter study that just concluded. Now the company is launching a phase III study as part of an effort to petition the Food and Drug Administration for approval of GM-CSF as a treatment for Crohn’s disease.


Dieckgraefe BK, Korzenik JR. Treatment of active Crohn’s disease with recombinant human granulocyte-macrophage colony-stimulating factor. The Lancet, vol. 360, pp. 1478-1481, Nov. 9, 2002.

This research was supported by a General Clinical Research Center grant from the National Institutes of Health. Yeast-derived recombinant human GM-CSF and financial support were provided by the Immunex Corporation. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or the writing of the report.

On the basis of Dieckgraefe and Korzenik’s hypothesis, Washington University applied for a patent covering the use of colony-stimulating factors for the treatment of Crohn’s disease. After submission and acceptance of this manuscript, the technology was licensed by Washington University to Berlex Laboratories Inc. Brian K. Dieckgraefe, Joshua R. Korzenik and Washington University School of Medicine’s Department of Medicine are entitled to a share of the royalties received by the University from the licensed technology. The terms of these arrangements are being determined by the University in accordance with its conflict-of-interest policies (

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.