Safe and effective therapy discovered for patients with protein-losing enteropathy

December 06, 2007

(December 6, 2007 - La Jolla, CA) Researchers at the Burnham Institute for Medical Research (Burnham Institute) have developed the first model to study intestinal protein leakage in mice, allowing the team to control and replicate both genetic deficiencies and environmental damages in an in vivo setting. Protein-losing enteropathy (PLE) encompasses conditions that involve the abnormal leakage of blood proteins into the digestive tract. One type of PLE is observed in children who have undergone Fontan surgery, a procedure used to alleviate certain congenital heart defects. Half of post-Fontan patients who develop PLE die from this condition, due largely to therapeutic options that are inadequate and accompanied by serious side effects.

A study performed by the laboratory of Hudson Freeze, Ph.D., at the Burnham Institute has been published in the Journal of Clinical Investigation (JCI), describing both the science behind PLE and also a way to treat the disease that side steps some of the severe complications of current treatments.

Dr. Freeze's group, led by Lars Bode, Ph.D., identified commonalities in clinical observations of PLE patients that recognized several key features of PLE pathogenesis; in particular, it is episodic and its onset is often associated with viral infection and a proinflammatory state. The most intriguing commonality that the group observed in PLE patients is the specific loss of heparan sulfate (HS) from intestinal epithelial cells during PLE episodes. Importantly, the study revealed that loss of HS is a key factor in promoting protein leakage and makes the intestine more susceptible to inflammation and increased hypertension. Co-author Simon Murch, M.D., University of Warwick, UK, first noticed the loss of intestinal cell HS in one of their previous collaborations.

"When heparan sulfate is missing, the inflammatory molecules pack a much greater punch and impact than when HS is there on the cell surface," said Dr. Freeze, who is Professor and Co-Director of the Tumor Microenvironment Program at Burnham Institute.

The group had previously observed that soluble heparin compensates for loss of heparan sulfate and prevents protein leakage in vitro. However, long-term therapy with anticoagulant heparin has severe side effects, including bleeding, thrombocytopenia and osteoporosis. However, the study also revealed an alternative form of heparin as a potential therapy. By adapting well-established clinical assays to assess intestinal protein leakage in mice, Dr. Freeze's team found that a heparin analog, 2,3-de-O-sulfated heparin, also prevented protein leakage both in vitro and in mice without causing bleeding. This compound exhibits greatly reduced anticoagulant activity, compared to unmodified heparin, which may mean that it can be used safely at much higher doses to treat PLE.
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The PLE studies performed by the Freeze laboratory are funded by a gift from the Children's Hearts Fund (CHF), in association with the Women and Children's Hospital of Buffalo Foundation, whose mission is to fund research on the causes of, and cures for, complications following cardiac surgery in children. Thanks to CHF, Dr. Freeze's group will continue to work on further understanding the mechanism behind PLE, which may lead to better and safer alternative therapies for this devastating disease.

Dr. Bode received support for these studies from a research grant awarded by the Deutsche Forschungsgemeinschaft in Germany.

About Burnham Institute for Medical Research

Burnham Institute for Medical Research conducts world-class collaborative research dedicated to finding cures for human disease, improving quality of life, and thus creating a legacy for its employees, donors, and community. The Institute is headquartered in La Jolla, CA where it was established as a nonprofit, public benefit corporation in 1976 and is now home to three major centers: a National Cancer Institute-designated Cancer Center; the Del E. Webb Center for Neurosciences, Aging and Stem Cell Research; and the Infectious and Inflammatory Disease Center. In 2006, Burnham established a center for bionanotechnology research at the University of California, Santa Barbara. Burnham is currently establishing a campus at Lake Nona in Orlando, Florida that will focus on diabetes and obesity research and will expand the Institute's drug discovery capabilities. Today, Burnham employs more than 800 people and ranks consistently among the world's top 25 organizations for its research impact and among the top four research institutes nationally for NIH grant funding. For additional information about Burnham and to learn about ways to support its research, visit www.burnham.org.

Sanford-Burnham Prebys Medical Discovery Institute

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