PROGRESS IN PLE RESEARCH in 2007
Hudson Freeze, PhD, Burnham Institute for Medical Research, La Jolla,
Our last research update came your way in the Spring of 2007. Do we have anything new to report in the last six months? Yes, we do. As you may remember we published three papers in the last several years using funding from the CHF and a “starter” grant from the National Heart Lung and Blood Institute, one of the National Institutes of Health. In those papers, we laid solid foundations to help us understand how multiple factors contribute to PLE and how we might stitch them together to devise better therapies. This foundation then allowed us to make “designer” mice with altered genes making them more susceptible to developing PLE when given the right trigger. And that is exactly what happened. Our paper describing those results will be on-line soon (December 6) at one of the top medical journals, Journal of Clinical Investigation (JCI). We feel this is quite an accomplishment since PLE is not well known and the standards of the JCI are extremely high. Fortunately, they emphasize the importance of translational aspects of papers they accept (only about 20%). Our paper describes both the science behind PLE and also a way to treat PLE with a modified heparin that does not have the complication of anti-coagulation. This type of heparin is now in clinical trials for other medical conditions, not PLE. Whether it can or will be tested on post-Fontan children with PLE is uncertain for now.
Publication of our work in the JCI is an important milestone because it puts both PLE research in a brighter spotlight. This makes it more likely to be read by other physicians and scientists in diverse fields who actively seek connections to their own work. You may wonder why we would want or need to attract attention of other fields. The answer is that science and medicine advance by cross-fertilization of ideas; the more experts who see very well done science/medicine, the more minds are thinking about the seminal ideas and results reported in the medical and scientific literature. Inevitably, all researchers ask the next question of “why” does something work in a certain way. What is the mechanism? This is where we are now. How does heparin therapy (or the new modified heparin) actually work? For a few years we thought that heparin simply absorbed certain inflammatory molecules in the blood before they could cause intestinal protein loss. Heparin was just acting a sponge soaking up these molecules. Now we believe that it may be a sponge and more. It turns out that intestinal cells have a layer of sugar chains that look much like heparin—its called heparan sulfate (HS)—and that HS actually participates in transmitting the signals within the cell that cause protein leakage. When HS is missing, as it is in post-Fontan PLE patients, the inflammatory molecules pack a much greater punch and impact than when HS is there on the cell surface. We are working on the detailed mechanism of that interaction—the next “why”! Getting a better understanding may give us more (and better) ideas about additional therapies.
For example based on some of our results, we tested the ability of a molecule called curcumin—the intense yellow colored substance in curry powder—for its ability to suppress protein leakage. We found it did block some protein loss and we are exploring this in more detail in the coming year.
It may mean that increased consumption of curcumin might be helpful in treating PLE. It is possible. However, we need to do more work to convince ourselves that it is true. We can be hopeful, but we need to be cautious as well. We will keep you posted on our progress, which is sometimes agonizingly slow.
We expect to have another publication on line in Nature Clinical Practice, Gastroenterology and Hepatology (Janurary, 2008). That one address the subject of therapy direcly. We became aware that a young, N-glycosylation-deficient (not post-Fontan) woman in the Netherlands was suffering from severe PLE. Based on our results, we approached her physician with the idea of using heparin therapy. He agreed and she was treated with a combination of normal heparin by infusions and injections. This relieved her PLE within several weeks, and that improvement was maintained for several months. She has had some relapses since that time, but is now stable and has returned to college. What ask ourselves, “what we do not yet understand about heparin that reduces its potency over time?” Perhaps the non-anticoagulant heparin we described in our JCI paper on PLE in mice would do a better job. We do not know at this time.
Going forward now we have to focus much more on the basic mechanisms of how PLE develops at the cellular and molecular level. That’s where the real answers and new insights will come from. Our scientific and medical colleagues always ask these questions. Ultimately, they must judge the quality of our science and how well our discoveries advance the fundamental understanding of the entire process; we cannot only focus on finding a new therapy.
Solving those molecular details can be slow and tedious, and it is much less satisfying than finding a “breakthrough”, especially when lives are at stake. We are working on the mechanism of PLE and on the next generation of “designer mice” that will better mimic actual PLE than we can now. We hope that focusing on these areas will generate more substantial funding from the NIH for our lab to do PLE research. CHF can’t be expected to do it all! But for now, our work on PLE has to rely on the generosity of your gifts to the CHF. Help us as we try to help you, the families with PLE children. Help us live up to our Institute’s motto: From research…the power to cure.