Friday, October 05, 2007

Crohn's Research Info

Research - The Latest News
Third Quarter, 2007

Dear friends,

In recent months, we've gained additional important insights into the specifics of how Crohn's disease develops. Having identified many of the genes, immune factors, and bacteria that combine to cause the disease, we're now beginning to understand how these "disease partners" actually work.


Let's look at this emerging picture from several viewpoints:

Bacteria: Normally, the colon and the lower portion of the small intestine are "colonized" by a complex variety of bacteria, viruses, and fungi—collectively called the microbiota. Most of these are harmless, but occasionally, a bacterium can undergo a change and become virulent. Researchers are beginning to understand precisely how a common bug like E. coli can turn aggressive, and how it manages to attach itself to and invade the cells lining the small intestine where it can trigger Crohn's disease in genetically susceptible people.


Immune Dysfunction: Once virulent bacteria invade the intestinal cells, the immune system typically kicks in and mounts an attack to clear them. That's what happens if you're healthy. But if you're genetically predisposed to Crohn's disease, your immune system may get its signals crossed and overreact, leading to uncontrolled inflammation, or conversely, fail to kill the invader, leading to persistent infection.
As we've recently come to understand it, the immune dysfunction seen in Crohn's disease may manifest itself as:

1. a decrease in a person's ability to kill bacteria;
2. an overactive T cell response to bacteria and bacterial antigens;
3. an inability to tolerate the presence of commonly tolerated bacteria; or
3. changes in the intestinal cells that make it easier for bacteria to attach to them.

Genetics: Interestingly, the most recent gene to be implicated in Crohn's disease is ATG16L1, which codes for a protein involved in a process known as autophagy. The word "autophagy" literally means "eating oneself." In biology, it can be understood as the digestion within a cell of materials produced by that cell or from a bacterium engulfed by the cell. In people who have an abnormal variant of ATG16L1, the immune cells responsible for killing bacteria may not be up to the job, and bacteria may resist being destroyed.
The discovery of ATG16L1 fits almost uncannily with recent insights into what goes awry in at least some types of Crohn's disease. A defect in ATG16L1 may lead to problems with autophagy, while a defect in NOD2—the first Crohn's susceptibility gene to be discovered, in 2001—may impair the ability to kill bacteria through another route: by causing a deficit in the secretion of defensins, proteins that specialize in bacterial killing. These two genetic defects correlate with two different routes into the development of Crohn's disease, and with the new molecular insights described above.

It is hoped that a more detailed picture of the biology of Crohn's disease and ulcerative colitis will shape the search for improved therapies. The more we understand about the many factors that lead to the uncontrolled inflammation seen in these diseases, the more we can target "upstream," pre-inflammatory processes for treatment and nip inflammation in the bud.

Clinical News: One highly promising treatment for Crohn's disease, called natalizumab, has received preliminary endorsement by the FDA's advisory panel and is awaiting final approval. Natalizumab is an antibody against alpha-4 integrin, a protein involved with the recruitment of immune cells to the site of inflammation. Natalizumab blocks that recruitment process, thus short-circuiting the inflammatory response.
If approved, the new drug could be a welcome alternative for people who have not responded well to anti-TNF agents. Currently approved for the treatment of multiple sclerosis (MS), natalizumab was briefly taken off the market because three people developed progressive multifocal leukoencephalopathy (PML), a rare brain infection, while taking the drug. For this reason, natalizumab is being used in a very select group of patients with MS who are being monitored very closely for side effects. It will be used similarly in people with Crohn's disease if it receives final FDA approval.

The drug's safety issues have drawn attention to a far broader problem: the anti-inflammatory therapeutic strategy itself. By damping down inflammation, a key function of the immune system, the medications used to treat inflammatory diseases may put patients at risk for infection. The risk may be small, but we should and can do better.

All in all, the news is encouraging. We've already got the big picture, and now we're homing in on the details. And the details are what we need to more fully understand if we're going to find our way to better treatments and, perhaps sooner rather than later, a cure. Please continue to support our efforts to the greatest extent you can. The quality of life of millions of people depends on it.


R. Balfour Sartor, M.D.
Chief Medical Advisor
Crohn's & Colitis Foundation

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