"Isolating this gene is a critical step towards improved diagnosis of this disease and developing better therapies for Crohn's sufferers," says Katherine Siminovitch, a U of T professor with the Department of Medicine. She is also a senior scientist at the Samuel Lunenfeld Research Institute at Mount Sinai Hospital and a founding scientist at Ellipsis Biotherapeutics Corp. "There's an urgent need for better treatment for patients with Crohn's."
Crohn's disease is an inflammatory bowel disease and its prevalence is increasing in industrialized nations. Existing treatments are considered unsatisfactory, often requiring recurring hospitalization and surgeries. Using DNA samples from family groups, Siminovitch and her research team employed a technique called positional cloning to first locate the chromosome containing the gene and then identify the gene. Their findings appear online April 11 in Nature Genetics (www.nature.com/ng/).
The gene isolated by the researchers produces a protein that sits on the cell surface and regulates how substances enter and exit the cell. In a majority of Crohn's disease patients, this protein functions improperly and allows toxins easier access to the cell.
The ability to test for this protein malfunction will help physicians distinguish between Crohn's disease and ulcerative colitis, the other major form of inflammatory bowel disease known. The malfunction is not present in ulcerative colitis, so this gene alteration provides a diagnostic test to help distinguish between the two diseases. Siminovitch says that this information can also be used to diagnose Crohn's disease at an earlier stage and to develop new approaches to treatment. She and her fellow researchers are now working on the development of a chemical that would alter the protein to restore its normal function.
Their findings should shed additional light on the basic causes of chronic inflammation, knowledge that will be invaluable to researchers. "The inflammatory processes that lead to disease are very similar in many chronic, common conditions, such as Crohn's diseases and rheumatoid arthritis, even though the target organ may be different," Siminovitch says.
Ellipsis Biotherapeutics is currently investigating the mutant protein's effects on cell function to with the eventual goal of developing of therapeutics.
However, Siminovitch says there is still much more work to be done in understanding Crohn's disease. "This isn't the only gene involved in Crohn's disease and there are also disease-causing interactions between genes and environmental factors, about which we know very little," she says. "If we can identify the majority of the genes involved in this disease, we can learn how these genes act together to cause disease. This information will help us identify potentially preventable environmental triggers as well."
Other U of T researchers were Bill Newman, David Cescon and Gordon Greenberg, (also at Mount Sinai Hospital), Laurence Rubin (also at Ellipsis and St. Michael's Hospital), Anne M. Griffiths (also at the Hospital for Sick Children) and Vanya Peltekova and Peter St. George-Hyslop (also at Ellipsis). Richard Wintle and Mark Van Oene of Ellipsis Biotherapeutics and Christopher Amos, Qiqing Huang and Xiangjun Gu of the University of Texas also contributed to the research.
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