How Donations Are Used
CURED supports and is a part of the Consortium of Eosinophilic Gastrointestinal Researchers (CEGIR). CEGIR is a network focusing on 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 public.
CURED contributes meaningfully by leading from within CEGIR and also donating $25 thousand to CEGIR’s initiatives. To read more about CEGIR and the CURED Foundation, click here.
CURED Foundation provided funds and/or grants at the below facilities:
CEGIR
CEGIR was founded in Fall 2014 with an NIH grant (U54 AI117804). The NIH 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 donations fund trainees located across the United States and novel exploratory projects. Trainee research includes (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. The CEGIR CURED donation is helping CEGIR to make great strides to find treatments and cures for Eosinophilic Gastrointestinal Diseases.
Children’s Hospital Colorado – Dr. Glenn Furuta
University of Illinois at Chicago – Dr. Steven Ackerman
Studies about the Esophageal String Test
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.
Cincinnati Children’s Hospital Medical Center – Dr. Marc Rothenberg
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Research conducted by the Rothenberg CURED Laboratory has drawn attention to the potential key cytokine mediator of EGID, the thymic stromal lymphopoietin (TSLP) cytokine. Genetic variants in the TSLP gene are the strongest risk factor for EoE, compared with all other genetic variants across the whole genome. Furthermore, the TSLP protein is over-produced in the inflammatory tissue of patients with EGID, and TSLP induces type 2 immune responses that are germane in EGID. With funds from the CURED Foundation, the Rothenberg CURED Laboratory has found that overexpression of the TSLP gene induces EoE-like responses. We have determined that the mechanism is dependent, at least in part, on IL-13, and interestingly not on eosinophils, consistent with recent human data that eosinophil depletion does not improve clinical outcomes in patients with EoE. Furthermore, while TSLP has a role in the development of atopic diseases in other tissues, we are finding a much more important and specific role in the esophagus. Additionally, we have found that the effect of TSLP is not limited to the innate immune system (e.g. epithelial cells, mast cells, and eosinophils) but is important for the memory arm of the immune system (adaptive immunity), particularly at the level of pathogenic food antigen-driven T cells. These findings are not only scientifically interesting but also have great potential to be immediately clinically applicable, as anti-TSLP antibody therapeutics are now being developed. The first anti-TSLP drug, Tezepelumab (Tezpire), has just been approved as an add-on maintenance treatment for adult and pediatric patients aged 12 years and older with severe asthma. Based on our research, multiple companies are already carrying out, or planning to carry out, clinical studies of anti-TSLP drugs for the treatment of EoE. It will be important for the Rothenberg CURED Laboratory to continue to pursue the scientific elucidation of TSLP in EGID so that its employment in patients is optimized, based on high-level scientific investigations. CURED funds allow for the continuation of the scientific pursuit of research concerning TSLP involvement in EGID.
Marc Rothenberg, MD, PhD
Director, Division of Allergy and Immunology, Cincinnati Children’s
Director, Cincinnati Center for Eosinophilic Disorders, Cincinnati Children’s
Director, Consortium of Eosinophilic Gastrointestinal Disease Researchers
Publications
First study: Investigated genes and gene variants across the human genome associated with eosinophilic esophagitis.
The first study 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.
Publication / Press Release link(s):
Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis
Common variants at 5q22 associate with pediatric eosinophilic esophagitis
Second study: Further investigation into which genes and gene variants are associated with eosinophilic esophagitis.
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.
Publication / Press Release link(s):
Study Finds Cause of Mysterious Food Allergy, Suggests New Treatment Strategy
Cytokine interleukin 13 (IL‑13) in eosinophilic esophagitis
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.
Publication / Press Release link(s):
Gene expression was used to design a test to predict whether an individual with eosinophilic eosinophilia has eosinophilic esophagitis.
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.
Publication / Press Release link(s):
Molecular diagnosis of eosinophilic esophagitis by gene expression profiling
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.
Publication / Press Release link(s):
Two protein receptors were shown to regulate the high eosinophil level.
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.
Publication / Press Release link(s):
Specific microRNAs have been shown to be involved in eosinophilic esophagitis, including microRNA 21, 223, and 375.
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.
Publication / Press Release link(s):
Diagnostic, functional, and therapeutic roles of microRNA in allergic diseases
MiR-223 deficiency increases eosinophil progenitor proliferation
Targeted ablation of miR-21 decreases murine eosinophil progenitor cell growth
DSG1 was found to have a role in causing eosinophilic esophagitis.
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.
Publication / Press Release link(s):
Until this study, the gene expression, tissue and immune features of eosinophilic gastritis had not been thoroughly described.
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.
Publication / Press Release link(s):
Advancing the Understanding of an Understudied Food Allergy Disorder — Eosinophilic Gastritis
CDH26 is increased in both the esophageal tissue in eosinophilic esophagitis and the gastric tissue in eosinophilic gastritis.
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.
Publication / Press Release link(s):
Key Function of Cadherin-Like 26 in Eosinophilic Gastrointestinal Disorders
Molecular diagnostic panel of eosinophilic gastrointestinal disorders
Ann & Robert H. Lurie Children's Hospital Of Chicago – Dr. Joshua Wechsler
CURED is funding projects that address key questions in EoE by the Wechsler CURED Lab.
Question: How can we identify optimal patients for diet elimination and what specific foods should be eliminated?
Project Goal: The Wechsler Lab will perform studies to validate biomarkers of the response to diet elimination treatment and specific food triggers to enable testing at the time of diagnosis.
Question: What is the role of mast cells in EoE?
Project Goal: The Wechsler Lab will perform studies on mast cells isolated from biopsies, specific mast cell proteins, and mouse models of EoE using mice that are missing key proteins vital to mast cells.
Question: Beyond eosinophils, what is the optimal cell to identify EoE severity?
Project Goal: Recent studies have informed the limitation of eosinophils as a biomarker of inflammation in EoE. The Wechsler Lab will assess the difference in mast cells and T-cells based on the response to dietary changes, quality of life, connective tissue disorders, and severity of scarring.
Question: How does scar tissue form in EoE and how is it best treated?
Project Goal: The Wechsler Lab will perform cellular and molecular studies on patients who underwent EndoFLIP, which quantifies scar tissue severity, to assess the cellular interactions and pathways that drive scar tissue formation. In addition, the Wechsler lab is assessing which specific therapies best improve esophageal diameter and lessen the formation of scar tissue.
Prospective Confirmation of the Molecular Signature of Dietary Therapy Responses and Triggers
This study aims to validate the three gene panel that Dr. Wechsler’s laboratory identified with prior support from CURED. The gene panel predicts the outcome of single versus multiple food triggers of EoE to understand more about dietary responses and triggers. Ultimately, a test for biomarkers of trigger foods would allow clinicians to identify the optimal food(s) to eliminate for each child. This would help reduce trial and error, as well as reduce the need for multiple endoscopies. Progress includes:
- Collected an increased number of tissue samples (100 versus the anticipated 60)
- Completed RNA isolation from these samples
A Novel Investigation to Examine the Role of Mast Cells in EoE
This research will provide an increased understanding of the role of mast cell inflammation and activation in EGIDs. Found in most tissues throughout the body, mast cells function as environmental sensors to trigger the immune system. This research is critical to identify the need to quantify mast cells as a treatment outcome and identify novel therapeutic targets to care for patients with EGIDs.
- Obtained two prospective cohorts of children with EoE and controls with which to identify peripheral biomarkers of mast cell inflammation
- Developed an artificial intelligence (Al) algorithm that is more accurate that standard methods to quantify mast cells
- Received a $25,000 grant to support our work to determine if mast cell density in EoE patients is increased with co-morbid connective tissue disease
Dr. Wechsler’s research will lead to new diagnostic and treatment options to improve the lives of children with EoE. Support from CU RED has been crucial to his efforts and will ultimately transform care for patients living with EGIDs.
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
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.
Northwestern University – Dr. Paul Bryce
Ann & Robert H. Lurie Children’s Hospital of Chicago – Dr. Joshua WechslerThe 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.
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.
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.
Rady's Children's Hospital San Diego-Dr. Seema Aceves,
Fibroblast Characterization and Functional Role in Eosinophilic Esophagitis
The Aceves lab is grateful to CURED for funding our studies on the mechanisms and clinical impacts of esophageal remodeling. We are working to determine the changes in esophageal fibroblasts that occur during active EoE as compared to the healthy esophagus. Our approach is to use fibroblasts from EoE patients and compare them to healthy esophageal fibroblasts using sequencing, proteomic, and functional techniques. Our data show new findings that EoE fibroblasts have a decreased ability to break down pro-inflammatory products like adenosine triphosphate (ATP) to anti-inflammatory products like adenosine. The impact on fibroblasts is that their function is altered in the way they respond to their extracellular environment in terms of gene expression and wound healing. These studies allow us to pursue new ways to remedy the pathologic changes that occur in EoE fibroblasts which should help us to find new strategies for treating complications such as esophageal rigidity and narrowing. Additional ongoing projects include understanding how immune activation is occurring in fibroblasts and if these changes can be used to gauge the severity of the clinical course. To better understand tissue and cell changes, we are pursuing new ways to evaluate esophageal tissue using intact mucosa and imaging using multiple antibodies. This should help us understand how the localization of cells changes during EoE and as compared to a healthy esophagus.
Massachusetts General Hospital - Dr. Caitlin Burk
Tracking T-cell receptors in Food Triggered Eosinophilic Esophagitis
Caitlin Burk, MD is an allergist/immunologist at Massachusetts General Hospital (MGH). She studies specialized allergic T cells that are involved in EoE. Dr. Burk has recently discovered that certain aspects of these cells in the blood are different between individuals with active EoE, with EoE in remission, and without EoE. She is hopeful that additional work may lead to blood biomarker tests for EoE diagnosis and monitoring, and eventually underlie T-cell-specific treatments for EoE.