Oct. 12, 1999 SEATTLE -- Researchers say they have discovered a reversible lipid imbalance that may be responsible for the common symptoms of cystic fibrosis. The discovery, in mice carrying the genetic defect that causes cystic fibrosis, could lead to a treatment for a disease that affects an estimated 30,000 people in this country, according to Juan Alvarez MD PhD and Steven Freedman MD PhD of Beth Israel Deaconess Medical Center in Boston.
Alvarez and Freedman reported their findings today at the Cystic Fibrosis Foundation's annual scientific conference in Seattle. The researchers are working with the foundation and the biotechnology company Genzyme General, of Cambridge, Mass., to develop a treatment for cystic fibrosis.
To date, research on treatments for cystic fibrosis has focused on gene and protein therapies and antibiotic drugs. The discovery reported by Alvarez and Freedman points toward a new approach to treating the disease--one that relies on correcting a fatty-acid imbalance in the membranes of cells affected by cystic fibrosis. The researchers propose that the imbalance is the source of the chronic lung inflammation, excess mucus, and other symptoms of the disease. "They've made some tantalizing observations in an animal model," said Peter Durie MD, director of cystic fibrosis research at The Hospital for Sick Children in Toronto, where the cystic fibrosis gene was discovered 10 years ago. "No current therapy for cystic fibrosis deals with the underlying problem. Potentially, this is something closer to the fundamental problem."
In the study reported today, Alvarez and Freedman examined differences in the relationship between levels of two fatty acids in normal mice and mice that had the genetic defect responsible for cystic fibrosis. They found that the cystic fibrosis mice had abnormally high levels of arachidonic acid (AA) and abnormally low levels of docosahexaenoic acid (DHA) compared to normal mice. The lipid imbalance was confined to organs most affected by cystic fibrosis, including the lungs, pancreas, and intestine.
To test whether the imbalance between AA and DHA was responsible for the expression of the disease, large doses of DHA were fed to the cystic fibrosis mice for one week. The researchers found that administration of DHA not only corrected the lipid imbalance in affected organs but also reversed the signs of cystic fibrosis in the pancreas, intestine, and lungs of the mice.
Alvarez and Freedman said that preliminary evidence shows that a similar imbalance between AA and DHA exists in people with cystic fibrosis. They are continuing to study the relationship between AA and DHA in cystic fibrosis patients, under a research agreement with Genzyme established in June. Under a concurrent agreement with Beth Israel Deaconess, Genzyme has been granted an exclusive license to intellectual property related to DHA therapy. Patent applications have been filed on the discovery.
DHA is a fatty acid found in sources such as fish oils and breast milk and is available in over-the-counter nutritional supplements. The researchers caution that current formulations of these supplements will not be effective at the recommended doses or well tolerated at the high doses that may be required to achieve clinical effect. In previous studies of low doses of fish oil supplements to control lung inflammation, people with cystic fibrosis have shown no statistically significant clinical improvements compared to control subjects. Also, the main component of fish oil supplements is another fatty acid that may block the DHA action.
Genzyme General is collaborating with the BI-Deaconess researchers to develop a therapeutically effective formulation for a DHA-based product. Genzyme will also sponsor clinical trials of this potential therapy. The trials are expected to begin within a year.
"We are very encouraged by the results reported today by our partners at Beth Israel Deaconess," said Alan E. Smith PhD, chief scientific officer of Genzyme Corp. "Genzyme has a long-standing commitment to patients with cystic fibrosis. This collaboration expands the range of potential treatments we are exploring for this disease."
Genzyme has been at the forefront of cystic fibrosis research for nearly a decade. It has conducted eight gene therapy clinical trials in patients with cystic fibrosis and has also begun research to identify potential small-molecule drugs to treat the disease under a grant from the Cystic Fibrosis Foundation. Genzyme expects to conduct its clinical trials of a DHA-based product in collaboration with the foundation, which has established a specialized network of seven clinical trial centers to expedite the early phases of clinical trials.
"Although a number of steps remain before the benefit of DHA to patients is known, this exciting research represents an entirely new strategy to correct and possibly even prevent some of the ravages of this disease," said Robert J. Beall PhD, president and chief executive officer of the Cystic Fibrosis Foundation. "The discovery also illustrates a true partnership in action--as industry, academia and a private non-profit health organization come together to translate science in the laboratory into innovative new treatments for our patients. We are truly gratified that we could play a significant role in this discovery."
Cystic fibrosis is the most common fatal hereditary disease among Caucasians in the United States. The median life expectancy of patients with cystic fibrosis is 32 years. Cystic fibrosis is caused by a defective gene that affects multiple aspects of cellular function. The most debilitating consequence of the disease occurs in the lungs of cystic fibrosis patients, where abnormally thick, sticky mucus clogs the airways, leading to fatal lung infections.
Alvarez and Freedman are also exploring the relationship between AA and DHA levels and idiopathic pancreatitis, a disease that may also be due to mutations in the cystic fibrosis gene. Dr. Freedman expects to test the DHA-based product in patients with pancreatitis.
Beth Israel Deaconess is a major teaching hospital for Harvard Medical School and a founding member of CareGroup. Dr. Alvarez is research director for the obstetrics and gynecology department at Beth Israel Deaconess and an associate professor of obstetrics and gynecology and reproductive endocrinology at Harvard Medical School. Dr. Freedman is director of The Pancreas Center at Beth Israel Deaconess and an assistant professor of medicine at Harvard Medical School. The research of Drs. Alvarez and Freedman was supported by the Cystic Fibrosis Foundation, BI-Deaconess OB/GYN Foundation (Rosenfeld Fund), and the National Institutes of Health.
Genzyme General develops and markets therapeutic products and diagnostic products and services. Genzyme General has three therapeutic products on the market and a strong pipeline of therapeutic products in development focused on the treatment of rare genetic diseases. A division of the biotechnology company Genzyme Corporation, Genzyme General has its own common stock (Nasdaq: GENZ) intended to reflect its value and track its economic performance.
This press release contains forward-looking statements, including statements concerning the estimated U.S. cystic fibrosis patient population and the planned initiation of clinical trials. Actual results may materially differ due to numerous factors, including, among others, the accuracy of the parties' information about the incidence of cystic fibrosis in the United States, the results of the study concerning the relationship of AA and DHA in people with cystic fibrosis, the results of efforts to develop a therapeutically effective formulation for a DHA-based product, the timing and content of submissions to and decisions by regulatory authorities, and the enrollment rate for clinical trials.
Information for cystic fibrosis patients, including a summary of the presentation and Q&A, is available on the Cystic Fibrosis Foundation's web site at http://www.cff.org .
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