Monday, March 1, 2004
CF gene mutations may also be responsible for other ailments, researchers say.
By JAMIE TALAN
LONG ISLAND NEWSDAY
More than 50 years after cystic fibrosis was first identified as a disease, Harvard scientists have found a key puzzle piece -- an imbalance of fatty acids -- that may lead someday to a novel treatment for the lethal disease.
Dr. Steven Freedman, an associate professor of medicine at the Harvard Medical School, discovered that cystic fibrosis patients have much higher levels of arachidonic acid and depletions of docosahexaenoic acid. AA and DHA at normal levels keep cell membranes healthy. The study appeared recently in the New England Journal of Medicine.
About 30,000 people in the United States have cystic fibrosis. This genetic disease results from any one of 40 mutations on the Cystic Fibrosis Transmembrane Regulator (CFTR) gene. A mutation triggers a buildup of abnormally thick mucus in the lungs, pancreas and intestines. Symptoms develop in early childhood. Life-threatening lung infections take hold, and patients generally live only into their 30s.
Scientists hoped discovery of the cystic fibrosis gene in 1989 by Lap-Chee Tsui and colleagues at the Hospital for Sick Children in Toronto would herald a gene-therapy cure. But gene-therapy trials were unsuccessful, and scientists are still trying to find effective ways to deliver a healthy version of the CFTR gene.
Additional associations
This gene is large. What scientists now know is that there are almost 1,200 polymorphisms, or varieties, of the gene, and new studies suggest some varieties may actually be milder mutations that may be associated with common medical conditions.
Freedman said there is growing evidence that problems in the CFTR gene are associated with chronic pancreatitis, asthma, ulcerative colitis and male infertility. "These adult-onset conditions all involve an inflammatory defect of some kind ... and we are continuing to hunt for other conditions," Freedman said.
CF patients and even a parent with one CF mutation have a souped-up inflammatory response.
Freedman and his colleagues are still unraveling the genetics of the milder conditions. In CF, patients have two copies of the abnormal gene. In the adult-onset conditions, it may be that one gene variation from one parent will be enough to cause these conditions, or perhaps one from each parent. These polymorphisms are quite common. Freedman said his finding that there are fatty-acid imbalances can also be important for these other conditions.
Fatty-acid research
Two years ago, his team showed similar imbalances in the levels of these fatty acids in mice with cystic fibrosis. The researchers increased the levels of DHA in these mice, and their symptoms improved.
In the latest study, scientists analyzed tissue from 38 cystic fibrosis patients and found that levels of DHA were two times lower than normal and AA was two times higher. These fatty acids control important biological processes, including inflammation.
Freedman and his colleagues hope this new link can be used to usher in a new generation of targeted therapies. If fatty acids regulate inflammation, and inflammation is the major player in this illness, it is hoped that fixing this fatty-acid imbalance can stop the abnormal inflammatory response.
The team also studied tissue from parents of 13 CF patients. The parents, all with one copy of the defective gene, also had abnormal fatty-acid levels.
"This tells us that these abnormalities are key to the disease itself," Freedman said. He is now working with a pharmaceutical company -- Genzyme Corp. -- to develop an extremely high-dose DHA substance. "Correcting these imbalances could be what is needed to treat this disease," he added.
Freedman said about 50 percent of people with chronic pancreatitis have a CF mutation, as do 40 percent of people with chronic sinusitis and 33 percent of infertile men. Diabetes has also been associated with the CFTR gene.
Dr. Brian O'Sullivan, co-author of the study in the New England journal, is recruiting CF newborns to test the benefits of DHA-enriched baby formula, compared to traditional formula. Studies have shown that DHA, an omega-3 fatty acid, is critical for brain development and overall health.