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CEGIR (Consortium of Eosinophilic Gastrointestional Disease Researchers)
CURED both supports and is a part of the Consortium of Eosinophilic Gastrointestinal Researchers (CEGIR). CEGIR was founded in Fall 2014 with an NIH grant (U54 AI117804) and is believed to be the first to establish a network focusing on the three distinct diseases of eosinophilic esophagitis, eosinophilic gastritis, and eosinophilic colitis. CEGIR furthers research and clinical expertise, trains clinical investigators, supports pilot clinical research projects, and provides access to information related to eosinophilic disorders for basic and clinical researchers, physicians, patients, and the lay public.
The grant is funded by the Office of Rare Diseases Research, which is part of the NIH’s National Center for Advance Translational Studies, as part of the Rare Disease Research Network. This award is co-funded by the National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, and the National Institute of Allergy and Infectious Diseases.
CURED is one of the patient advocacy organizations that contributes meaningfully by leading from within CEGIR and also donates $25 thousand to CEGIR’s initiatives. Coinciding with Rare Disease Day® 2015, CEGIR launched a patient contact registry for individuals with eosinophilic gastrointestinal diseases.
The registry is located at www.rdcrn.org/CEGIR, and its purpose is to create a single, international database with information submitted by patients and their families. Establishing such a database will enable CEGIR investigators to identify and recruit patients for new research studies directed towards improving treatments and clinical care.
CEGIR is grateful to the CURED Foundation for its kind and enabling support. CURED funds have been used to fund trainees to pursue EGID research as well as funding novel exploratory projects. EGID research trainees are located at different institutions across the USA, highlighting the impact that CURED is having. The trainees research many different EGID projects such as (1) the interface between IgE-related mediated food allergy and EoE; (2) the mechanism of action of proton pump inhibitors in EoE; and (3) T cell-related factors that predispose participants in oral immunotherapy to develop EoE. Overall, the CEGIR CURED donation is helping CEGIR to make great strides to find treatments and cures for EGIDS! Thank you so much for your support!
Ann & Robert H. Lurie Children's Hospital of Chicago - – Dr. Joshua Wechsler
Read More on the two projects CURED has supported that are being done in Dr. Wechsler's Lab
Cincinnati Children’s Hospital Medical Center – Dr. Marc Rothenberg
A study was the first to investigate what genes and gene variants (of the >550,000 evaluated) across the human genome are associated with eosinophilic esophagitis. Risk for eosinophilic esophagitis associated greatly with a gene region called 5q22, which houses the gene for the cytokine called thymic stromal lymphopoietin (TSLP). TSLP was further investigated and shown to be involved in eosinophilic esophagitis.
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A second, more extensive genomic study further investigated what genes and gene variants (of the >2.5 million evaluated) across the human genome are associated with eosinophilic esophagitis. Risk for eosinophilic esophagitis associated greatly with a gene region called 2p23, which houses the gene for the protease calpain 14 (CAPN14). Proteases are proteins that take apart other proteins. CAPN14 was further investigated and shown to be involved in eosinophilic esophagitis. The reason why people develop an esophageal specific response in EoE was uncovered through this work.
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Several basic and pre-clinical studies showed the importance of the cytokine interleukin 13 (IL‑13) in eosinophilic esophagitis. These findings prompted a clinical trial using a protein (humanized antibody) that targets IL‑13, which showed some beneficial effects for patients. This clinical trial has led to collaborations with pharmaceutical companies to further test this and other possible therapeutics for eosinophilic esophagitis.
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Using knowledge gained through several studies of eosinophilic esophagitis, gene expression was used to design a test to predict whether an individual with eosinophilic eosinophilia has eosinophilic esophagitis. This test is now commercially available and being further developed.
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Genetics and environment both affect development of eosinophilic esophagitis. A study analyzing a large, international cohort of twins and siblings with eosinophilic esophagitis showed that environment is important and may have more influence than previously thought.
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Two protein receptors, paired immunoglobulin-like A and B (PIR‑A, PIR‑B), were shown to regulate the high eosinophil level, called eosinophilia, that is increased by interleukin 5 (IL‑5). IL‑5 is a central growth factor in eosinophil development and disease.
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MicroRNAs are small pieces of RNA that regulate the outcome of gene expression by interfering with the transcribed RNA of genes being translated into protein production. Specific microRNAs have been shown to be involved in eosinophilic esophagitis, including microRNA 21, 223, and 375.
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Tissue barriers are important throughout the body because they have to let certain things in and keep others out. In eosinophilic esophagitis, the esophageal barrier is too loose. The spaces between the cells forming the barrier are larger and let more in than normal. Desmoglein 1 (DSG1) is a protein that is involved in the cell‑to‑cell connections that form barriers. DSG1 was found to have a role in causing eosinophilic esophagitis.
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Eosinophilic gastritis is less well studied than eosinophilic esophagitis. Until this study, the gene expression, tissue and immune features of eosinophilic gastritis had not been thoroughly described. Eosinophilic gastritis and eosinophilic esophagitis were shown to have similarities and differences. In addition, eosinophilic gastritis was shown to be associated with more generalized eosinophilic gastroenteritis and blood eosinophilia in nearly all patients.
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Cadherin 26 (CDH26) is an adhesion protein. CDH26 is increased in both the esophageal tissue in eosinophilic esophagitis and the gastric tissue in eosinophilic gastritis. CDH26 is expressed by eosinophils and may be involved in how eosinophils target in on tissues. Ways to suppress CDH26 are being developed and tested.
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Children’s Hospital Colorado – Dr. Glenn Furuta & University of Illinois at Chicago – Dr. Steven Ackerman
The Esophageal String Test (EST) is a minimally invasive device that can be used to learn about underlying causes of EoE and to monitor disease activity in patients. Drs. Ackerman and Furuta continue to perform studies with the EST to validate it for clinical use by patients and to understand the mechanisms of EoE in order to develop new treatments.
The pathology of EoE involves remodeling of the esophagus that contributes to clinical symptoms such as dysphagia and food impactions. Drs. Ackerman and Furuta have performed studies identifying a pathway called Epithelial Mesenchymal Transition (EMT) that contributes to the development of esophageal fibrosis in EoE, and they are continuing to study how this process is induced and can be reversed.
University Of North Carolina – Dr. Evan Dellon
Validation of major basic protein and eotaxin-3 staining for diagnosis of eosinophilic esophagitis
With the support of this grant, we were able to validate a new way to diagnose EoE and help to distinguish it from gastroesophageal reflux disease (GERD). This study extended our prior preliminary work examining special esophageal biopsy staining (“immunohistochemistry”) for factors related to eosinophil inflammation and activation. Specifically, by looking at major basic protein (“MBP”, an eosinophil marker) and eotaxin-3 (a factor that draws eosinophils to the esophagus), as well as a different marker called tryptase (a stain for mast cells, another inflammatory cell involved in EoE), we were able to see that these were highly elevated in patients with EoE, but not highly elevated in non‑EoE control patients, including those with GERD.
We were able to develop an algorithm for measuring the staining levels, and have posted this on a website that is freely available for pathologists and clinicians to use to help gauge how likely the diagnosis of EoE is (https://gicenter.med.unc.edu/cedas/eoe_calculator.html).
The results have been published in Clinical Gastroenterology and Hepatology (2014; 12: 2015‑2022). This study could not have been completed without the support of CURED, and the diagnostic methods developed in this project can help with challenging clinical cases or diagnostic dilemmas.
Diagnosis and monitoring of eosinophilic esophagitis using the Cytosponge
This study, which is ongoing and currently enrolling patients, is examining the use of the Cytosponge, a new minimally invasive test, for diagnosis and monitoring of EoE. The Cytosponge is a foam sponge which is contained within a dissolvable capsule and attached to a string. The capsule is swallowed, dissolves in the stomach, the sponge expands into a sphere, and after 5 minutes is retrieved by a nurse by pulling the string. As the sponge is withdrawn, cells along the whole length of the esophagus are collected by the foam sphere, which allows an esophageal tissue sample to be obtained. The foam sphere, now containing cells, can be examined using standard pathology methods.
The main goals of this project are to assess the safety, acceptability, and accuracy of Cytosponge for diagnosis and monitoring of EoE in comparison to endoscopy and biopsy.
The study is being performed in a collaboration between University of North Carolina and Mayo Clinic. We hope that if this technique is effective, the Cytosponge may be an important way to assess EoE disease activity in the future without requiring an endoscopy and biopsy.
Northwestern University – Dr. Paul Bryce & Lurie Children’s Hospital of Chicago – Dr. Joshua Wechsler
The role of mast cells in persistent symptoms and abnormal endoscopic findings in pediatric Eosinophilic Esophagitis
Diagnosis of Eosinophilic Esophagitis (EoE), as well as effectiveness of therapies, is dependent on the presence of eosinophils within the esophagus tissue upon biopsy. Key to our proposal was the observation that many patients with symptoms of EoE show abnormal endoscopic findings and yet lack these cells in their tissue. Accumulating evidence has suggested the role of another immune cell, the mast cell, in EoE but their contribution to patients who lack eosinophils in unknown.
The support from CURED allowed us to examine the mast cell densities and phenotype in pediatric EoE and to examine these cells in patients who are classed as being in disease remission.
Using a comprehensive database that accumulates information from the medical records, endoscopic reports, allergy testing, and pathology of eosinophils and mast cells, and beyond, we have established new insights into the response to therapy, and mechanistic involvement of eosinophils versus mast cells. We believe that this research opens new avenues for therapeutic treatment of EoE and understanding the diversity of responses within patients.
The initial support from CURED was transformative in allowing us to establish this work and to obtain the preliminary data necessary for further funding applications to the National Institutes of Health.
Ann & Robert H. Lurie Children’s Hospital of Chicago – Dr. Barry K. Wershil & Research Team at Stanley Manne Children’s Research Institute
Molecular Targeting of Dietary Therapy for Eosinophilic Esophagitis.
Beginning last fall, CURED generously provided grant support for this study, which seeks to better understand and perfect the dietary therapy treatment approach. Through RNA sequencing and analysis of an existing clinical and biological patient database, Dr. Wershil and his team hope to be able to identify genetic markers that will be predictive of their response to dietary elimination therapies.
This result would allow for a more personalized, tailored treatment choice, easing the suffering of kids and families being seen and treated for EoE. We are so grateful to CURED for its shared interest in this unique research project. Its potential results could provide a better quality of life for so many diagnosed with this illness.