Cystic fibrosis gene linked to fatty acid defects

01/30/04

Findings could lead to new treatment for life-threatening genetic disease

BOSTON – The discovery that cystic fibrosis (CF) patients have an imbalance of fatty acids in their tissues could help pave the way for a new treatment of this genetic disease that affects approximately 30,000 people nationwide. These findings extend previous observations from mouse studies and show that the same fatty acid abnormality occurs in humans with CF, is related to the degree of abnormality in the gene, and is not a consequence of inflammation.

These new findings, described in a study led by researchers at Beth Israel Deaconess Medical Center (BIDMC), UMass Memorial Health Care (UMMHC) in Worcester, and Massachusetts General Hospital (MGH) appear in the Feb. 5 issue of The New England Journal of Medicine. Characterized by chronic inflammation of the lungs, CF results in the production of an abnormally thick, sticky mucus, which leads to the development of life-threatening lung infections. Although it was initially thought that infection itself led to eventual lung failure in CF patients, it is now recognized that an excessive host inflammatory response plays a major role in the process. About 1,000 new cases of CF are identified each year, with more than 80 percent of all patients diagnosed by age three. The median age of survival for people with CF in the United States is in the early 30s.

"Since 1989, we have known that the defective CFTR gene is responsible for CF," explains senior author Steven D. Freedman, MD, Ph.D., of the gastroenterology division at BIDMC and associate professor of medicine at Harvard Medical School. "But we didn't understand how this defective gene leads to the symptoms of the disease. This new study sheds light on what may be happening and provides a link between CFTR function and fatty acid metabolism."

"CF is a very complicated disease with a variety of factors at play at the cellular level. Research such as this could lead us to a new effective tool in the fight against CF," said Robert J. Beall, Ph.D., president and CEO of the CF Foundation and Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT). "We applaud this pioneering work by Dr. Freedman and his colleagues on fatty acids and CF and look forward to translating this work into a tangible benefit for patients."

Fatty acids are long molecules that serve as the building blocks of the cell membrane, which covers the outside of the cell. Certain fatty acids, such as arachidonic acid (AA) and docosahexaenoic (DHA) acid, are important in controlling a variety of biologic functions, including inflammatory responses. Earlier animal studies by Freedman and colleagues looked at differences in the relationship between levels of these two fatty acids in normal mice and in mice that had the genetic defect responsible for CF. These studies gave the first indications of the fatty acid imbalances in CF and that these imbalances may have significance in the development of therapeutic approaches.

In the new study, the researchers examined tissue samples of 38 CF patients to determine if they also exhibited an imbalance of these same fatty acids. As predicted, the results showed that there were abnormally high levels of arachidonic acid and abnormally low levels of docosahexaenoic acid.

"It is known that high amounts of AA and low amounts of DHA would predispose to inflammation," explains Freedman. "This discovery may help explain why there is an excessive inflammatory response among CF patients. This is the basis for why Omega-3 fish oils, found in cold-water fish as well as supplements, reduce inflammation since they increase levels of DHA and suppress AA."

The study also revealed that this fatty acid abnormality was unique to cystic fibrosis. According to Brian P. O'Sullivan, MD, who led the research at UMass Memorial Medical Center, in testing the parents of 13 CF patients (all of whom were known to carry one copy of the defective CF gene), it was discovered that the parents had fatty acid levels half-way between those of the CF patients and those of unaffected control subjects.

"The fact that individuals who carry the CF gene – but are otherwise healthy – have levels of AA and DHA midway between normal controls and CF patients is consistent with our hypothesis that a fatty acid defect is a basic problem in CF, and not just a reflection of a disease state," explains O'Sullivan.

"This degree of abnormality does not occur to the same level in other 'inflammatory' diseases such as asthma or inflammatory bowel disease," adds Freedman.

CF patients are typically treated with antibiotics and, to this point, research on new treatments has focused on symptomatic therapies and methods to improve CFTR function.

This study, as well as earlier ones also supported by CFFT, found that when the CF mice were given large doses of DHA, the fatty acid imbalance was corrected and signs of the disease were reversed. Freedman cautions that exceptionally high doses of DHA were required to treat the CF mice, and that over-the-counter supplements would not be beneficial and could be harmful at the high doses required to achieve clinical effectiveness.

Study co-authors include BIDMC researchers Paula G. Blanco, MD, Munir M. Zaman, MD, Julie C. Shea, BA, Mario Ollero, DVM, Isabel K. Hopper, RN, Deborah A. Weed, RN, Andres Gelrud, MD, and Meredith M. Regan, ScD; Michael Laposata, MD, PhD, of Massachusetts General Hospital; Juan G. Alvarez, MD, PhD, of Hospital San Rafael, La Coruna, Spain; and Brian P. O'Sullivan, MD, of UMass Memorial Health Care, Worcester, MA.

BIDMC owns issued and pending patents on novel methods for treating disorders in which DHA levels are affected, and has an exclusive licensing agreement with Genzyme Corporation for the development of therapies for CF.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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