PLE RESEARCH- 3/2007
Hudson Freeze Ph.D.
Burnham Institute for Medical Research, La Jolla CA
My lab receives funding from the CHF to work on understanding and treating PLE, especially for the post-Fontan population. What has come from your generous support? We made progress in basic research and therapeutics. In addition, to a clearer picture of PLE, it may surprise you to learn that the work may help us understand of the body's response to starvation that affects100 million undernourished children worldwide. We keep extending the work of Jim Colson and all those in the CHF.
Why does PLE strike? Why so long after the initial surgery? Who is at risk? What can we do about it?
Our work points to a combination of environmental factors in children with a weak genetic background. While the Fontan surgery can raise blood pressure in many patients, only some develop PLE, often related to infections or inflammation. We found that loss of molecules called heparin sulfate (HS), located at the base of intestinal cells, is a key factor in promoting protein loss through the intestine. We think that a genetic weakness in making HS puts patients at higher risk. The weaker it is, the more susceptible they are to developing PLE during those inflammation times. The combination of increased pressure from the Fontan operation, inflammation, and HS loss all conspire to initiate PLE. Our lab has worked on human cells in culture and on mice that are genetically engineered to have weakened HS. These mice are normal until they are challenged by inflammation and increased pressure put them all together and the trouble starts with massive protein loss. My associate, Dr. Lars Bode, Simon Murch and I have just submitted a paper on this work to a medical journal so that other doctors will know about this new perspective.
What about therapy? One of the mysterious therapies for PLE is giving injections of heparin. Our thanks goes to Jason Mikula for being the first pioneer to make this revolutionary observation and set us on the right track. When we tried heparin on our mice, it essentially prevented the protein loss. Heparin can have bad side effects because it prevents blood clotting and can lead to osteoporosis. So, we also tested a novel type of heparin without the clotting problems, and it works just as well as normal heparin. Based on all of this, we think that modified heparin might be useful for post-Fontan PLE patients who have failed to respond to heparin, since the modified version can be given at much higher doses. We are hopeful. In addition we continue to test other types of modified heparin as potential therapies in cultured cells, and if it works, we will move on to mice.
We think that it may be possible to identify patients at risk for developing PLE by checking for protein loss before their surgery. Perhaps they tend to be in the upper end of normal, which would indicate one risk factor. An intestinal biopsy at the time of surgery might also show some loss of HS already, placing them on the edge . Of course confirming that idea would need a multi-center clinical study. In time, we should be able to look for key genetic weakness factors that might predict loss of HS. While these are future studies, we are laying the groundwork for them now.
Our lab is also applying for larger grants from the National Institutes of Health (your tax dollars) to continue this work. It is a difficult time for obtaining grants, only about 1 in 10 is funded and even then, it is only at a fraction of the costs needed to do the work. Again, your contributions make the critical difference.
Speaking of making a difference, does our fundamental understanding of post-Fontan PLE have applications to other diseases. Yes, maybe it does. Patients with congenital disorders of glycosylation (CDG) sometimes get PLE and show that same loss of HS. Our new understanding prompted one physician in the Netherlands to use normal heparin therapy in one young adult CDG patient who had developed PLE. It was quite successful, worked within a few weeks, and continued for several months, but she has recently slipped a bit. Her doctor is now trying additional therapies, but has not yet used the modified heparin.
Our collaborator in the UK, Dr. Simon Murch, is a pediatric gastroenterologist who studies undernourished children in Zambia. You may have seen these sad pictures in which children appear either rail thin or bloated with distended stomachs. The second type is all too familiar to parents of post-Fontan PLE children. Why do these starving children from the same village living on the same diet look so different? This puzzled Dr. Murch too, and he analyzed the intestines from the two different groups. He found that the bloated children suffering from this condition called kwashiorkor had the same loss of HS that he sees in post-Fontan children, while the other group of emaciated children (marasmus group) had normal HS. This may mean that the same HS factors involved in post-Fontan PLE may underlie the different appearance between kwashiorkor and marasmus children. By developing our basic understanding of PLE in post-Fontan children, it might lead to a better way of treating children with kwashiorkor. Dr. Murch has an idea for an additional therapy for them, since simply re-feeding them can be fatal unless done with great care.
The motto of our institute is "From research, the power to cure". That is my lab's focus, and with your help, we will find everywhere our results can be