Tuesday, April 27, 2010

From Wall Street Journal - Unraveling Crohn's Genetic Trail

From April 27, Wall Street Journal In the search for the causes of irritable-bowel conditions like Crohn's disease, doctors had long focused on diet. But studies have repeatedly failed to show that foods are to blame.

Now, researchers are focusing on genetic mutations linked to these conditions. The hope: to develop a therapy that fixes those mutations in order to actually cure diseases like Crohn's and ulcerative colitis, rather than just treat the symptoms.

For more than 15 years, Warren Strober has been studying these diseases at the National Institute of Allergy and Infectious Diseases in Bethesda, Md. He and other scientists have shown that dozens of genes are linked to Crohn's and ulcerative colitis.

Dr. Strober's current work centers on developing a stem-cell-based therapy to correct one particular gene mutation for Crohn's. But the wide variety of mutations means that there could eventually be a number of different treatments that target patients based on their genetic profiles, a strategy known as "personalized medicine."

In irritable-bowel conditions, the immune system attacks harmless bacteria normally found in the gut. This response leads to inflammation of different parts of the digestive tract, which in turn can cause pain, fissures, abscesses and obstruction.

In Crohn's, the walls of the digestive tract become inflamed, and any part—from the mouth through the large intestine—can be affected. With ulcerative colitis, only the lining of the bowel is damaged. Together, the conditions affect about 1% of the U.S. population.

People with Crohn's can suffer from chronic diarrhea, abdominal pain, fever, fatigue and sometimes rectal bleeding. They may also have problems absorbing an adequate amount of nutrients from food, particularly if too much of the intestine is removed. The disease can stunt the growth of children.

Treatments have improved in recent years and now include powerful, injectable biologic medicines that reduce inflammation, such as Johnson & Johnson's Remicade and Abbott Laboratories' Humira.

But these therapies aren't cures, and not everyone responds to them. In severe cases, patients must undergo surgery—sometimes multiple surgeries—to remove parts of the bowel or colon that are blocked. For Crohn's, in particular, because it can develop in any part of the gut, inflammation can recur even after surgery in a different segment of the digestive tract. Within 10 years after surgery, 80% to 90% of Crohn's patients will have a relapse, according to researchers.

In their search for a cure, Dr. Strober says he and his colleague, Ivan Fuss, are "bounding ahead" on research in mice that aims to fix a genetic mutation called NOD2 associated with Crohn's. The idea would be to have the body repair itself by growing the corrected gene using so-called induced pluripotent stem cells.

Stem cells are those that can develop into different types of specialized cells, like heart or muscle cells, and are mostly found in embryos. Induced pluripotent stem cells, or iPS cells, are made by taking adult specialized cells and turning back the clock, engineering them to an earlier stage where they can reproduce again.

Dr. Strober's team has already figured out how to take cells from the intestine and convert them into iPS cells. Now, they are working on fixing the genetic defect in the iPS cells before testing the therapy in animals.

First, they take segments of human DNA that contain the NOD2 gene mutation and break the DNA apart. Then, like a puzzle, they reassemble the DNA except for the one broken piece—the gene mutation. That piece is replaced with a new, corrected piece of DNA.

After the gene mutation is corrected, the completed iPS cell will be administered into the bone marrow of mice with Crohn's disease, where the new intestinal cells that develop should be fully functioning again. They plan to begin testing mice later this year.

The biggest challenge with this type of "integrated science" approach—one that combines genetic information, physical symptoms and biology—is narrowing down which genetic combinations are critical to which patients, according to Stephan Targan, director of the division of gastroenterology and the institute for inflammatory bowel immunobiology at Cedars-Sinai Medical Center in Los Angeles.
Dr. Strober and others are also looking at different genetic and molecular pathways that could lead to better understanding and treatments for Crohn's and ulcerative colitis.  Other researchers are examining how genetic mutations affect the type of bacteria that are found in the digestive tract. Greater presence of certain types of bacteria may be more likely to trigger an immune response. Still another area of research focuses on understanding how individuals' genetic makeup can make them susceptible to certain other Crohn's triggers, such as stress, smoking and the use of nonsteroidal anti-inflammatory painkillers.


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