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Patients Needed for Clinical Trial
*** We are in need of post-fontan patients interested in participating in a Heparin Clinical Trial!
We are also looking for any Pediatric Cardiologist that has at least 3 post fontan patients that would be willing to speak with us regarding out current research. Please contact Hudson Freeze at the Burnham institute or reach us through info@childrenshearts.org
Time is of the essence as you all know. Thank you in advance for your consideration. ****
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| Dr. Hudson Freeze |
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We have made good scientific progress in this calendar year. Two papers appeared, one was just accepted and another is in revision for the Journal of Biological Chemistry. One publication in the Journal of Clinical Investigation on the basis of protein-losing enteropathy (PLE) garnered high praise in a New England Journal of Medicine feature article entitled “Patching a leaky intestine”. The other report in Nature Clinical Practice, Gastroenterology and Hepatology showed the beneficial effects of heparin in a non-Fontan PLE patient. Another recently accepted paper focuses attention on the molecular similarities between PLE and kwashiorkor, a form of childhood malnutrition producing bloated-bellies. Our other study focused on understanding how decreased N-glycosylation contributes to enteric protein loss has taken time to finalize.
An alliance between the Burnham Institute and Sanford Health of Sioux Falls, SD laid the groundwork for compassionate use/clinical trials of a modified heparin for PLE patients. The company controlling the modified heparin in the clinic has delayed any action on PLE use due to the world-wide shortage in the wake of the Chinese adulterated heparin scare.
In July, the March of Dimes Foundation funded a 3-year grant specifically to the effects of impaired N-glycosylation in PLE. Our final submission to the NIH to create a more refined model of PLE scored in the top 13% of all grants. Funding decisions will be made in February 2009.
Goals for the upcoming year will include more efforts to understand the basic science underlying the effects of N-glycosylation and heparan sulfate loss on the development of PLE. Specifically, CHF funding will be used try to investigate the use of human growth hormone as a potential therapeutic.
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Published Studies
Our primary goal is to understand the molecular basis of PLE and use this information to identify potential therapies. Most of our key results are found in the two attached papers that appeared in 2008 and that were summarized in the last report prior to their publication. Their importance is highlighted in a New England Journal of Medicine review of our work; it is also included. Proofs of our paper in press at the American Journal of Clinical Nutrition and abstracts from various meetings are included.
Our collaborator Dr. Simon Murch found that heparan sulfate is absent from basolateral surface of the intestinal epithelial cells during PLE in glycosylation-deficient and in post-Fontan patients. He also found loss of HS in children suffering from kwashiorkor, a protein-energy malnutrition condition characterized by swollen bellies. In contrast, children suffering from marasmus (also a protein-energy malnutrition state) have normal HS on their intestinal epithelial cells, but these children have no edema, and instead appear emaciated.
We hypothesized that protein starvation causes loss of plasma protein through the intestine even though there is little protein to spare. We found this was true. Additional studies on the link between enteric protein loss and kwashiorkor are needed to interpret these results, but some of the insights we developed here for this “rare” but devastating disorder, PLE, may have links to life and death issues of millions of children around the world
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In a few short years our laboratory has taken PLE from virtual scientific obscurity to a feature article in the world’s most highly cited medical journal. While we have been fortunate in making these discoveries and juxtaposing diverse observations into a coherent hypothesis, it is no accident. Providing a scientific rationale for the use of heparin in PLE patients is a substantial achievement. Therapies for human disorders, improvements on them, or providing rationales to underpin unconventional therapies in science occur all too rarely in basic scientific research.
Basic research is the main focus of my laboratory and a mixture of inspiration and excitement eventually prevailed over the uncertainty and risk inherent in turning a large portion of the lab toward PLE-related research.
To build and maintain momentum, to submit grant after grant application and to anticipate and respond to objections from peer reviewers about the work is part of the business of basic research, and yet without the support from the CHF, all momentum would have been lost and the project(s) dismantled here.
Maintaining this momentum is costly both in time and money.
The Children’s Hearts Fund enabled our lab to study PLE.
CHF’s contributions sustained the momentum and provided the bridging while we awaited word on whether any other funding would be forthcoming.
The symbiosis has worked well from our perspective, and the continued support will enable us to stay in the game and, NIH willing, expand from here.
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Scientific
We plan to continue exploring the mechanistic basis of the interaction of pro-inflammatory cytokines and their receptor and how loss of HS synergistically stimulates protein loss.
Specifically for the CHF funding, we are submitting a plan to investigate another therapy, human growth hormone. Post-Fontan patients do not grow and mature normally. An 18 you may appear 10-11, and a 12 you no more than 7. Why? Perhaps it is simply a consequence of the congenital heart problems, but we think it may be more complex. Anecdotal reports suggest that growth hormone (GH) or somatotropin improves PLE in a few post-Fontan patients, but there are no clinical studies to support the routine use of this FDA-approved drug.
There is a substantial literature on the beneficial effects of GH and protein/amino acid supplements for Crohn’s disease (CD) patients, who have increased intestinal permeability; the mucosal version of enteric protein loss. GH reduces intestinal permeability in CD patients. In mouse models and cell monolayers, GH counteracts the inflammatory effects of TNFa signaling through the NFkB pathway. We hypothesize that GH will also have positive effects on PLE.
We will determine whether providing GH to epithelial cell monolayers decreases paracellular protein leakage and whether providing GH to mice decreases their enteric protein loss under multiple experimental conditions. If GH is effective, these results would support the use GH therapy for post-Fontan PLE patients.
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