Target: celiac disease: therapies aimed to complement or replace the gluten-free diet

Science News, June 21, 2003 by Ben Harder

Not many kids can imagine a world without cereal, pizza, or cookies. But these are just a few of the foods that Stanford University biochemist Chaitan Khosla has had to teach his 6-year-old son to avoid. The boy has celiac disease, an inherited immune disorder, and it has sentenced him, for life, to refrain from eating anything that contains wheat gluten or similar proteins in barley and rye. In the boy's small intestine, those grain components would trigger a chain of events that can cause bloating, diarrhea, and malnutrition. Without the restricted diet, the condition can lead to fatigue, migraines, dermatitis, anemia, and osteoporosis.

Khosla's son isn't alone in enduring his gluten-free lifestyle. Although celiac disease was considered rare in the United States a decade ago, recent tallies indicate that it may affect as many as 1 in 150 people, or 2 million in all. Many people with the condition aren't properly diagnosed and suffer unexplained symptoms and potentially grave complications.

Before an astute pediatrician diagnosed celiac disease in Khosla's son, the researcher had never heard of the disease. Neither had his wife, although she'd had gastrointestinal and skin problems for years. "She was one of the hundreds of thousands of misdiagnosed [people] out there," Khosla says.

People in whom the disease is recognized must give up not only most grain-based foods but also soups, sauces, canned foods, and hundreds of other items. Manufacturers frequently ada gluten to those processed foods, and they charge hefty premiums for products prepared instead with rice proteins or other innocuous additives.

After sugar, Khosla says, gluten is the second most prevalent food substance in Western civilization. At a typical supermarket, "chances are you're not going to be able to fill a grocery bag with gluten-free products," he notes. Raising a young child to be accordingly vigilant about what he or she eats is "gut-wrenching," Khosla says. If the pun is intended, his solemn tone doesn't betray it.

With the aim of releasing his son, wife, and other people from their strict, lifelong diets, Khosla and other scientists have turned their attention to therapeutic alternatives that could short-circuit the, disease's development. The fight drug might block the degeneration of the intestinal lining--the hallmark of celiac disease.

The researchers' latest findings offer new insights to the disease's biological mechanisms and an unprecedented understanding of at least three potential molecular targets for drugs.

The challenge ahead is to develop medications that can effectively strike these targets in the body. Although the trigger for symptoms comes from the diet, celiac disease--which is also called celiac (or coeliac) sprue, and gluten intolerance--is not an allergy. It's more similar to complex immunological disorders such as multiple sclerosis, insulin-dependent diabetes, and rheumatoid arthritis, for which effective drugs have proven difficult to develop.

Even if scientists can devise a drug for celiac disease, it might complement the gluten-free diet rather than fully supplant it. Nevertheless, Khosla maintains hope that a prescription pill for celiac disease will exist by the time his son goes to college, 11 years from now.

TAKING AIM Because gluten is a complex protein, normal digestion doesn't completely break it down. Surviving pieces called peptides come in contact with the lining of the small intestine and the molecules of the immune system there. Whether that molecular encounter results in the immune overreaction at the heart of celiac disease depends on the type of immune molecules present.

Nearly all people with the disease have one of two immune-molecule types: About 90 percent carry so-called DQ2 molecules, and most of the rest carry DQ8 molecules. Genetics determines whether a person has either or both of these disease-associated molecules. For reasons not yet understood, a few people develop celiac disease despite having neither DQ2 nor DQ8 molecules, and not all people with the molecules develop the disease.

Early in both normal digestion and the pathological cascade that marks celiac disease, an enzyme called tissue transglutaminase (tTGase) alters gluten peptides. When these altered peptides encounter DQ2 or DQ8 molecules in the intestine, they form molecular complexes that activate immune cells called T cells, which then mount an attack on the intestinal lining.

Under the assault, that stretch of the digestive tract becomes inflamed and loses the fingerlike projections, or villi, that normally provide a vast surface area for absorbing digested nutrients. Many of the symptoms of celiac disease, including malnutrition and anemia, develop in response to the small intestine's reduced effectiveness in absorbing nutrients.

To forestall this cascade from occurring when a person with the disease ingests gluten, a drug could potentially dismantle all gluten peptides into their individual amino acids. That approach essentially treats gluten as a pathogen, Khosla says, and aims to detoxify the protein before it can cause trouble. Since the feat would probably require some sort ofpeptide-destroying enzyme, or peptidase, researchers refer to this approach as enzymatic therapy.