Countering Crohn’s Disease

Counterintuitive thinking helped devise a means to treat this gastrointestinal malady



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.

“I look forward to my shot each day. It’s hard to put into words how wonderful I feel. I feel like a normal person.”


“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. Oddly enough, it appears to work.”



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.






Kelly Perkowski was 20 when she was diagnosed with Crohn’s disease, a chronic, lifelong condition that affects about half a million people in the United States.

“I had symptoms for a couple of years before I actually knew what was wrong,” says Perkowski, who for a time got symptom relief from taking steroids.

When her medications just weren’t working anymore, Perkowski considered surgery. Her doctor suggested that she might want to try one more thing first—speak with a Crohn’s disease researcher and gastroenterologist at Washington University School of Medicine.

Joshua Korzenik, MD, had recently arrived at the School of Medicine from Yale. The assistant professor of medicine was kicking around ideas with Brian Dieckgraefe, MD, PhD, also an assistant professor of medicine in the division of gastroenterology and a staff physician at Barnes-Jewish Hospital.

“From the start, it’s been a very nice collaboration,” Korzenik says. “Brian is primarily in bench science. 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.”

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. That treatment strategy works to improve symptoms in many Crohn’s disease patients, but a large number, like Kelly Perkowski, don’t get relief.

Dieckgraefe had been 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 working with Korzenik, 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 is thought to result from an impaired immune response, they looked at other genetic diseases that also impair immunity.

“There are probably 100 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.”

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 their Crohn’s disease symptoms if these patients with genetic immune diseases were treated with drugs that actually enhanced their innate immune response?

Joshua Korzenik, MD, right, and Brian Dieckgraefe, MD, PhD, followed an unlikely route in their study of Crohn's disease.

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. Called G-CSF (granulocyte colony stimulating factor) and GM-CSF (granulocyte macrophage colony stimulating factor), the 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,” says Korzenik. “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 reports 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. Kelly Perkowski was one of them.

“In less than two weeks, my symptoms vanished,” she says.

Patients in the study took daily injections of GM-CSF, also known by the trade name Leukine® (sagramostim). 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 a large-scale, multicenter study to see if the findings can be replicated. At present, patients at more than 30 centers in the United States are receiving injections each day to test the idea that for some patients with Crohn’s disease, enhancing immunity might work as well, or even better, than impairing it.

The idea is so promising and different that it’s been patented. On the basis of Dieckgraefe’s and Korzenik’s preliminary findings, Washington University applied for a patent covering the use of colony-stimulating factors for the treatment of Crohn’s disease. Subsequently, the new technology was licensed by Washington University to Berlex Laboratories Inc.

“This work represents a wonderful example of technology transfer,” says Theodore J. Cicero, PhD, vice chancellor for research. “The financial benefit related to this technology might help to support future research, both studies involving these investigators and work done by others at Washington University.”

If a daily injection of GM-CSF can relieve their symptoms, or even put them into remission, many people with Crohn’s disease will line up for the treatment.

“I look forward to my shot each day,” Perkowski says. “It’s hard to put into words how wonderful I feel. I feel like a normal person.”