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Potentially Safe and Effective Therapy Revealed for Patients with Protein-Losing Enteropathy
December 07, 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.
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.
Burnham Institute for Medical Research
"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.
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.
Burnham Institute for Medical Research
tTGA: Is it more essential in diagnosis of gluten sensitive enteropathy?
CD is a highly prevalent disease (1:100 to 1:300) which fulfils most of the criteria favoring mass screening. Despite this, screening for gluten sensitive enteropathy (GSE) is still controversial due to its dubious benefits and the acceptance of a gluten-free diet (GFD).
The prevalence of gluten-sensitive enteropathy in iron-deficient anemia patients
Gluten sensitive enteropathy (GSE) is an autoimmune enteropathy due to food gluten intolerance in genetically predisposed people.
A rare case of collagenous colitis presenting as protein-losing enteropathy
Since the first report in 1976, collagenous colitis has been associated with a variety of conditions, including use of non-steroidal anti-inflammatory drugs and proton pump inhibitors.
Researchers identify gene responsible for rare childhood disease
The chromosomal abnormality that causes a rare, but often fatal, disorder that affects infants has been identified by researchers at the University of California, San Diego School of Medicine, who happened to treat two young children with the disease in San Diego - two of perhaps a dozen children in the entire country diagnosed with the disorder.
Cocktails ameliorate celiac disease
The University Rovira i Virgili (Spain), the company Trace Biotech AG (Braunschweig), the Institut für Mikrotechnik Mainz GmbH (IMM, Mainz), and seven other European partners are jointly developing a biosensor for the detection of gluten in food. The goal of the ambitious project is to manufacture a disposable microsystem with integrated modules for a standardised extraction and analysis of gluten in food samples. The system, for the first time, will permit patients suffering from celiac disease (gluten sensitive enteropathy) to conduct an on-the-spot analysis of fresh, cooked, or industrially processed food with the aid of a screening procedure. The project is funded with more than 3 M
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