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PLE Research Update
September 2004
Dr. James G. Colson
Finding the cause and cure of Protein-losing Enteropathy (PLE) remains a world wide effort. The obvious approaches involving hemodynamics, the immune system and infection, among others, have been largely unsuccessful. The reasons are many, but the main one is a lack of PLE patients with similar histories. After several Symposia held locally with international experts and funded by our Children?s Heart Fund ($30,000 each) , we have decided to approach the problem in two ways not yet undertaken - one clinical and one experimental. The first approach is clinical under the guidance of Dr. Jack Rychik at the Children?s Hospital of Philadelphia. Our Fund supplied a Grant of $150,000 under the concept that the primary hypothesis for the cause of PLE is a condition characterized by all or some of the following:
1) Abnormal mesenteric (intestinal) blood flow
2) Inflammation
3) Abnormality in coagulation proteins,
4) Neurohormonal response.
Initial results verify the first three. No neurohormonal response is found. While these results are statistically significant at the 90% level, they lead us to no obvious clinical response! We..await the inclusion of two more PLE patients to raise our confidence and thereby suggest clinically proper avenues. A year end completion date is probable.
Our second approach is driven by the fact that heparin injection is one of the few treatments that have given temporary relief from PLE symptoms. Unfortunately, all PLE patients do not respond and with most the efficacy wears off after some years of treatment. Over the last few years we have funded a $60,000 Research Grant at the Burnham Institute in San Diego to better understand the role of heparin and the use in PLE. We established the first in vitro tissue culture model mimicking PLE-like protein leakage. Our results show that loss of heparin sulfate (HS) directly causes protein leakage in this model. However, reasons why Fontan patients lose HS during episodes of PLE need to be further elucidated.
Our results also provide an explanation for the favorable response to heparin seen in some post-Fontan PLE patients. Heparin and HS are structurally related and we hypothesize that the addition of soluble heparin compensates for the loss of cell-associated HS.
With the above excellent results we have decided to continue funding this effort with a Grant of $32,000 to fund the following work. Although heparin alleviates PLE in some post-Fontan patients, it can exert undesirable side effects due to its anti-coagulative properties. Therefore, we have started to screen a library of heparin-like molecules for their effects on protein leakage in our in vitro tissue culture model. We aim to identify heparin-like molecules with a similar or even higher potential to alleviate protein leakage, but without exerting anti-coagulative effects.
To transfer our in vitro results to the in vivo situation, we aim to establish a mouse model of PLE and to assess the contributions of HS loss, pro-inflammatory cytokines, and increased pressure to intestinal protein leakage in vivo. With this model we will also test whether heparin or heparin-like molecules/oligosaccharides mitigate or even prevent PLE. In the long run these results might not only shed light into the underlying mechanisms of PLE, but may also pave way for an efficient treatment of PLE in humans
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