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Canadian team lifts hopes on Crohn's

Defective gene can be pinpointed with ‘extremely easy' test

A group of Canadian scientists has found a gene carried by 50% of Crohn's disease sufferers, leading to hopes of a drug treatment.

As many as 35,000 Canadians have Crohn's, an inflammatory bowel condition so painful many patients take morphine to cope.

One key problem is the difficulty of diagnosing the condition at an early stage.

In a study published in Nature Genetics , researchers from the University of Toronto report isolating a genetic mutation that permits toxins to enter the lining of the intestines. They suspect it damages the gut, leading to painful inflammation.

“Like all common diseases, Crohn's isn't caused by a single gene defect,” says study co-author Katherine Siminovitch, a professor of medicine at the University of Toronto. “What happens is you would have this gene defect and probably a few more. And that would make you predisposed.”

The most common Crohn's symptoms are stomach pain, often the lower right quadrant, and diarrhea. Rectal bleeding, weight loss and fever may also occur. The bleeding can be serious, leading to anemia. Children with Crohn's may suffer delayed development and stunted growth.

Crohn's treatments, which include drugs to suppress the immune system are not much help. Sufferers are often forced to race to hospital with unbearable pain, sometimes for surgery to remove portions of their intestines damaged by the disease.

One problem for doctors is distinguishing Crohn's from another major form of inflammatory bowel disease, ulcerative colitis. Isolating the gene means a test could be developed quickly.

“This is an extremely easy test to do,” Dr. Siminovitch says. “It's a very simple thing that uses standard technology that any DNA lab could do.”

In the study, Dr. Siminovitch and her research team collected genetic samples from families with Crohn's sufferers. Because they were recruited from hospital programs, the patients tended to have severe disease.

Using a technique called positional cloning, the researchers pinpointed a gene that makes a protein that lies on the surface of cells. Known as a transporter, the protein is a kind of door that lets materials enter and exit the cell's interior. In about 50% of Crohn's sufferers, this protein is defective, making the cell wall “leaky”.

“ You don't want to transport in too many bad things that will then get into your system,” Dr. Siminovitch says. “We think that this transporter, when it has this [defective], is not working properly. It can let things in that shouldn't get in. And our translation of that is that it's probably causing initial damage in the gut lining and then predisposing to inflammation and the disease.”

By helping doctors diagnose Crohn's at an earlier stage – for example, people with a family history could be screened in childhood – the researchers hope to halt the disease before it ravages the gut.

Experts believe some things in the environment could be triggering these diseases, whose prevalence is rising in industrialized countries.

The findings could also shed light on other kinds of chronic inflammation and their causes.

“The inflammatory processes that lead to disease are very similar in many chronic common conditions, such as Crohn's disease and rheumatoid arthritis, even though the target organ may be different,” Dr. Siminovitch says.

She added that a treatment for Crohn's based on the gene finding may not be difficult to develop. She and other researchers have formed a company, Ellipsis Biotherapeutics, to work toward this goal.

“We now know what the protein does,” she says. “What we want to do is improve its function. And because it's a transporter, that many be not too difficult to do, because it's right there on the cell surface.”

Good things really do happen when people work together as witnessed at the celebration of the CH.I.L.D. Foundation, Variety – the Children's Charity and BC Children's Hospital Foundation on June 21, 2004.

Dr. Grace McCarthy, President of CH.I.L.D (Children with Intestinal and Liver Disorders), joined Will Webster, Chair of Variety when they presented a cheque in the amount of $2 million to Sue Carruthers, President, BC Children's Hospital Foundation, who contributed $1 million to establish the CH.I.L.D. Foundation Endowment for Pediatric Gastroenterology Research.