Amanda Cordell spoke to prof. Marc Rothenberg, director of the Division of Allergy and Immunology, Cincinnati Center for Eosinophilic Diseases, and the principal investigator at the Consortium of the Eosinophilic Gastrointestinal Disease Researchers, generally known as CEGIR.

They discussed the professor's professional journey, pivotal moments in eosinophilic research, leading organisations advancing research and care, and the future of diagnosing, treating, and monitoring these diseases.

Listen to this podcast episode on Spotify , watch or read the interview below.

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Dr. Rothenberg: 

Earlier Years

I was just a curious kid who would make observations and ask to explain things other people wouldn’t notice. In high school, I became interested in chemistry and set up a chemistry lab in my bathroom.

My mother, who is insulin-dependent, has taken well over 100,000 injections in her life to keep her alive, which inspired me to know the power of medicine and research.

I was always in search of excellence and wanted to align myself with the greatest scientific minds like the late Professor William Jenks, who taught me how to ask fundamental questions about simple processes. Or the late Professor K Frank Austin, one of the leading inflammatory researchers in immunology.

I went to medical school and got an additional PhD in immunology to understand how the body protects and repairs itself.

Interest in eosinophils

My interest in eosinophilia was serendipitous. Working on a related cell type, mast cells and basophils, and ran an experiment on basophils, using eosinophils as a control. We discovered that eosinophils survived longer than anticipated, which was against the current paradigm at the time. 

These results led to the discovery of eosinophilic mediators like IL-5, GM-CSF, and IL-3. Over the next 20 years, we saw the development of antibodies and proved that anti-IL-5 therapy was very useful for treating various diseases in patients. This eventually led to the FDA approval of a new class of medications based on this work following my PhD.

I pursued paediatric training to help people by intervening early in children’s diseases, with the potential to reverse conditions by modifying immune memory and tolerance. I did my postdoctoral research in the Department of Genetics at Harvard, where I was already training for the pre-decade. 

Phil Leader, the chairman of genetics, was an amazing mentor and scientist and had a peripheral interest in allergies. In his lab, along with my colleagues, we discovered and cloned the family of chemokines. I continued pursuing this interest by exploring a unique pathway that cooperated with IL-5, understanding how eosinophils accumulate in tissue through the eotaxin family, which regulates activation and chemotaxis.

Cincinnati Children’s

This work led to further insights into the life cycle of eosinophils and, eventually, my recruitment to Cincinnati Children’s, an amazing place formed in the US in 1931 with a rich history in paediatric research.

I love the team we’ve built here; they are great people interested in Eosinophilic Oesophagitis (EoE) and related issues.

We helped to put this area on the map by initially describing the disease, developing animal models, and revealing that it’s linked to food allergies rather than intrinsic immune issues.

Our work in discovering specific mediators laid the groundwork for the first FDA-approved precision therapies for these diseases.

As you know, the antibody against the IL-4 receptor has been a pillar of this work. It’s been a long journey. I feel blessed to be inspired by patients like EOS Network and organisations who have supported our research and to work with remarkable colleagues.

My goal remains to cure these diseases, an ongoing quest in the lab.

Dr. Rothenberg: 

Yes, there have been a number of key pivotal moments, some involving unexpected results. I always tell people in my lab that they can work on anything they want as long as they produce results rapidly and publish papers. The best results, to me, are the ones that prove my theories wrong.

One of the most unexpected observations was a recent finding.

After over 20 years of research on eosinophilic diseases, we reported that in EoE - a disease characterised by eosinophilia - there is a remarkably selective accumulation of eosinophils.

Diagnosing this disease requires counting eosinophils to meet agreed-upon thresholds, and we demonstrated this through various experimental systems.

Unexpected research findings

Finally, we adapted a technique we call the “essential human knockout,” previously used in mice, to safely eliminate eosinophils in patients using new drugs developed after a long research period. We predicted this would have a huge impact on helping patients and were very excited to do this experiment in humans.

After all the work involving research sites in many countries, we found that, as planned, the eosinophils were almost entirely removed from the patients. But, unexpectedly, the patients did not show clinical improvement. Read more about the study.

The results truly transform the field because they suggest that, even though we call this EoE, and the signals we use to monitor and diagnose the disease - eosinophils, rise to extraordinary levels - they are not the primary driver of the disease. So, this is a pivotal moment.

It greatly impacts patients and changes the field by making us rethink our approach.

It’s giving us pause in reconsidering how to diagnose and potentially monitor the disease and, of course, how to develop future therapies. These therapies may not focus solely on lowering eosinophils or monitoring treatment effectiveness based only on eosinophil levels, which is what we’ve often done in the past and what the FDA and other regulators have indicated is very important. 

Dr. Rothenberg: 

There’s certainly now an exciting amount of precision therapies in development. These include drugs like benralizumab, which can block different immune system components and do so relatively safely.

Our research has shown the allergic arm of the immune system is primarily vestigial and can be eliminated.

We can eliminate eosinophils and knock out a major pathway, like the one blocked by dupilumab.

This is encouraging for the future because there are a number of other ways to interfere with or block the allergic arm of the immune system.

There’s a series of new targets and drugs in all stages of development, including late-stage trials, which I predict will have a big impact on EoE and related EGIDs.

In our research, we are heavily invested in developing proof of concept for many of these therapeutic strategies.

But we’re also aiming high because, ultimately, the main goal for patients is not to have to take medications.

I’m encouraged by the fact that some of the greatest breakthroughs in this century have been in medical research on the immune system, such as immunotherapy in cancer treatment and mRNA vaccines for COVID-19.

I predict that we will see widespread applications of this research. These technologies had an impact that I hope will help reverse eosinophilic GI disease and allow patients to reeducate their immune systems and lead normal lives without chronic medications.

Professor Marc Rothenberg with his team at Cincinnati Children's Hospital, 2024

Dr. Rothenberg: 

Over the years, we made unexpected discoveries about EoE. Early on, if you’d asked almost anyone what caused the disease, they would have said acid reflux and would treat it with anti-reflux drugs like proton pump inhibitors (PPIs).

We subsequently showed we can elicit EoE not with acid but with allergen exposure in animal models. And that led to the idea that EoE was an allergic oesophagitis driven by immune hypersensitivity to food allergens.

This is important because, typically, EoE does not occur in isolation. It usually appears in atopic individuals - those with allergic conditions like eczema, asthma, hay fever, or food allergies.

Atopic March

We now understand allergies as a spectrum, with transitions from one to another. These can coexist in an individual or occur at a population level, with varying ages of onset. This pattern is often described as the “atopic march”, a simplified way to explain these associations.

EoE is part of this spectrum. Most EoE patients have comorbid allergic diseases, though EoE is often the more substantial, chronic issue, with higher morbidity than other atopic conditions, which tend to wax and wane.

But that’s not true for all patients. Some have widespread inflammation, with eosinophils in the blood and severe skin issues, often as a part of a syndrome linked to genetic causes and family history. We’ve identified the genetic basis for this and genetic susceptibility areas related to common EoE presentations, which has been very informative.

EoE Comorbidities and Associations

EoE is a part of the atopic march and is an atopic disease with related comorbidities. But we’ve also discovered that EoE can be associated with other conditions, such as inflammatory bowel disease (IBS), celiac disease, and hypermobility (joint laxity), which can include symptoms like fainting and blood pressure instability (POTS). Living with a chronic disease like EoE or other EGIDs is a challenge.

It can impact behaviour and psychological well-being. And it is tough. But I’m impressed with people with these diseases and their achievements.

Patient support groups like the EOS Network are important to bring people together, inspire them, and provide support at all levels.

Dr. Rothenberg: 

This is a really good question. The gold standard for diagnosing and monitoring eosinophilic GI disease is endoscopy, which requires a visit to the doctor, sedation, and, for children, undergoing anaesthesia.

Anaesthesia carries risks, and these procedures need to be repeated to monitor the patients, as there’s currently no acceptable marker for the disease outside of endoscopy. This procedure is costly, time-consuming, and invasive.

We are heavily invested in developing a blood test for EoE. We have made progress with that, particularly with molecules and proteins in the blood, that have great potential to become the reliable markers we need - an alternative to the current gold standard of biopsy.

Biomarkers are biological indicators that mark a disease or a phenotype. The ideal would be a blood test to diagnose and monitor EoE.

Biomarkers Examples

An example of a similar biomarker is the blood test used to diagnose and monitor prostate enlargement in men: a prostate-specific antigen. 

My lab is looking for what we call an eosinophil-specific antigen and EoE-specific antigen. I hope to share the progress we made in this regard with you in the near future. 

But there are a number of other markers in the developement, different types of molecules, such as microRNAs.

In my lab, we keep on the cutting edge of breakthroughs that are taking place in different fields and apply them rapidly to allergy problems with a strong focus on EoE. Certain fields lead and pave the way; I think cancer leads the way.

Less Invasive Tests

One of the things you’ve seen and a lot of your members may even be thinking about getting is blood tests for cancer that we now have.

Liquid biopsies is an idea that you can take a blood test and get biopsies of different tissues, which is very interesting for the oesophagus biopsies. 

Besides these, there are so-called less invasive tests that are available now, such as string tests.

A string test is when you swallow a string, wait and pull it out. String then goes to a lab, and they measure different proteins that they take off the string.

Transnasal endoscopy allows to pass a small tube (endoscope) through the nose and down the throat in a conscious, awake individual, including children. It can be used for less invasive oesophagus monitoring and, potentially, areas below the oesophagus.

There are imaging studies that use radiolabeled markers or tracers - substances with a small, safe amount of radioactive material that patients swallow to monitor inflammation. 

What’s exciting is that, just ten years ago, none of these options were available. We still don’t have a standard noninvasive blood test for EoE. But based on current data, if we revisit this in ten years - hopefully much sooner - we’ll likely see transformative research that significantly improves how we monitor and diagnose this disease.

Understanding Clinical Trials

Dr. Rothenberg: 

CEGIR started about 12-13 years ago. CEGIR’s goal is to understand, educate and treat patients with eosinophilic GI diseases through, as you said, collaborative research.

CEGIR is a partnership with the key stakeholders of the disease. It’s a cooperative agreement with the NIH (National Institute of Health), funded by three different institutes: NCATS (National Center for Advanced Translational Research), the NIAID (National Institute of Allergy and Infectious Diseases), and the NIDDK (National Institute of Diabetes and Digestive and Kidney Diseases).

They are not just funders but active participants, with NIAID leading our partnership.

Consortium of the Eosinophilic Gastrointestinal Disease Researchers (CEGIR) members, 2019

Patient Groups

The primary groups in the US are the CURED Foundation, which campaigns for research on these diseases; the American Partnership for Eosinophilic Diseases (APFED) group; and the Eosinophilic Family Coalition (EFC).

We are pleased to partner with you, Amanda, and the EOS Network.

We also have a group in Australia, AusEE, and other international partners. CEGIR primarily involves 18 leading sites across the US, working together to solve the mysteries of these diseases, along with key stakeholders worldwide, including partners in Europe and pharmaceutical companies invested in this research.

The funding also comes from some of these groups, such as CURED and APFED, and, more recently, some of the institutions.

Major supporters include Cincinnati Children’s, Colorado Children’s, and the University of Colorado, along with contributions from the other 16 institutions in various ways.

Of course, they’re supporting us by fostering the great researchers and clinicians - too numerous right now to count, as each has wonderful people contributing to this work. Nearly 100 people work daily to advance the understanding and treatment of these diseases.

Educational and Career core

Part of CEGIR’s mission is to educate the next generation of leaders in the field. We identified over 20 people in the early stages of their careers and are developing mentorship plans to allow them to benefit from CEGIR’s emerging data.

One of the studies in CEGIR is a longitudinal observational cohort following a thousand people with different types of EGIDs over time.

We use that data to uncover the natural history of the disease and to ask fundamental questions on diagnosis, monitoring, and developing standardised tools. These questions are critical for regulatory agencies when approving drugs in clinical trials, including methods like eosinophil counting, which is not a trivial matter. And we do have a whole core of expert pathologists involved in that.

One of the great things about CEGIR is its dynamic nature; it changes over time. Just today, we discussed how to use the latest information to build internationally recognised guidelines with global partners, aiming to improve diagnosis, treatment, and understanding of these diseases. This work is done in partnership with key stakeholders, especially regulatory agencies, with CEGIR mainly involved in collaborative work with the FDA.

Join EOS Network

Dr. Rothenberg: 

Thank you. Amanda, it’s my honour to do this, and I’m busy because of opportunities like this: being inspired and trying to partner with the patients to make their lives better. And this is one step along that process. I want to give you a round of applause for what you are doing with your organisation.

Thank you to all your supporters and members for advancing the field and bringing attention to this important disease, all in an effort to improve the lives of those suffering.

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Related articles:

Dupixent® Effective for Young Children with EoE: Positive Phase 3 Trial Results

Removing Animal Milk Vs Removing 6 Foods as EoE Treatment (CEGIR)

Overcoming The Inequalities in Eosinophilic Gastrointestinal Disease Research (CEGIR)

Questions and Answers about EADs With CEGIR

Capsule Sponge Study (Cyted)

Sponge-On-A-String Device (EndoSign®)

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