Newsletter - issue 1 2024

NEWSLETTER

Welcome to the first issue of the METHYLOMIC Project Newsletter!

We are excited to share updates on our progress with all our stakeholders.

This newsletter will be released quarterly, aiming to keep everyone informed about the significant developments and achievements within our consortium.

 

Read the newsletter

 

Recap Work Package 5 year 1

Andrew Li Yim and Anje te Velde lead the team in WP5 of the METHYLOMIC project, alongside Wouter de Jonge, Peter Henneman and Femke Mol. In its inaugural year, this team aims to discern whether DNA methylation signals originate from methylation itself or variations in cellular composition. Utilizing advanced single-cell technologies, they target specific DNA methylation patterns unique to various cell types. The following text provides a summary of the first year of research within WP5.

Single-cell technologies

The goal of work package 5 is to understand the origin of the observed DNA methylation signal of the predictor CpGs. Simply put, does the signal originate from actual DNA methylation, or a difference in cellular composition. To this end, we aim to pinpoint specific DNA methylation patterns that are unique to different cell types. To achieve this, we’ve looked for single-cell technologies that are capable of characterizing the cellular composition based on gene expression while simultaneously quantifying the DNA methylome at a single-cell level. Our strategy integrates two methodologies: smartSeq2 for characterizing cell populations via RNA expression, and reduced representation bisulfite sequencing (RRBS) for exploring the DNA methylome.

First step

The first step is to isolate white individual white blood cells from blood samples, followed by the isolation of both DNA and RNA from each cell. Ultimately, this will result in a paired DNA methylome and transcriptome per cell, for which we will develop a novel bioinformatic pipeline to dissect and interpret the data.

We anticipate that one of the challenges lies in the complexity of the blood samples. Blood encompasses different cell types, including erythrocytes, leukocytes, platelets, and plasma. In context of inflammation, our focus narrows down to the leukocyte fraction. Yet, within this subset there are more subdivisions: granulocytes, lymphocytes, and monocytes. Granulocytes are particularly challenging due to their susceptibility to degradation after collection.

Blood samples

We are now getting ready to put our techniques to the test using blood samples from volunteers with the goal of optimizing the protocol necessary to conduct the final analyses on samples obtained from patients that are scheduled to start treatment. We anticipate that our observations will provide insights into the mechanisms by which response manifests, potentially allowing us to refine existing treatments and pave the way for novel therapeutic interventions.

Text: Femke Mol

 

 

Helmsley grant for clinical validation trial OmiCrohn

Extra funding

The AMC has been awarded funding for the rapid targeted methylation assay development and partial funding for the clinical validation trial through a Horizon Europe grant award. Therefore, AMC also seeked co-funding from Helmsley Charitable Trust to close the gap in funding for the clinical validation trial. In 2023 funding was granted by Helmsley  to support the following clinical validation trial activities:

  1. Project site and data management that is aligned with the strict regulatory agency standards to allow the future submission of the trial data and analysis for regulatory approval of the assay.
  2. Central reading of endoscopies to enhance the overall quality of the trial.
  3. Training, quality control, and central reading for intestinal ultrasound (IUS) in one-third of trial participants. IUS transmural healing will be an exploratory outcome for the proposed trial.
  4. Processing of biopsy samples and central histology reading for analysis of disease activity.
  5. Recruitment boosting activities across the countries of the participating clinical sites including remittance of investigator participation fees, site staff training, periodic trial newsletters, and a national kick-off and two national site meetings of the investigators.
  6. Trial oversight, scientific support, and medical writing for clinical trial reports and publications.

Background information

There is an urgent need to develop biomarkers that are predictive of a Crohn’s Disease patient’s response to biologic therapies. If successful, this project will clinically validate a rapid targeted methylation marker blood test for the selection of the biologics adalimumab, vedolizumab and ustekinumab that has the highest likelihood of providing effective treatment for an individual Crohn’s Disease patient, decreasing the potential for delays in effective treatment and improving outcomes for Crohn’s Disease patients. Furthermore, the proposed study is designed to meet the criteria for future submission of the validated predictive assay for regulatory agency approval and therefore paves the way for the critical future steps that will be required to bring this potentially valuable tool into clinical practice.

Patients' questions about METHYLOMIC

What is epigenetics

Wouter de Jonge, professor of Experimental Gastroenterology, Amsterdam UMC:

Epigenetics is a broad term for the control panel for our genes. It involves changes to our DNA that do not alter the genetic code itself but can influence how DNA will be used in the cell. These instructions can be influenced by various factors, such as our environment, lifestyle, and even experiences. Epigenetics does not only affect DNA, but also structures wrapped around our DNA, so-called histones. It is a very complex process. Epigenetic changes can impact our health by affecting how our genes function, not only influencing our risk for certain diseases but also influencing the effect of different drugs on our bodies. In the OmiCrohn trial we will use patients’ individual epigenetic “blueprint” in DNA to predict the effect of different therapeutic options.

Three questions for Andrew Li Yim, Bioinformatician, Tenure Track Assistant Professor Amsterdam UMC

How does epigenetics affect immune disease?

I believe that in most case it is unclear how epigenetics exactly affects immune diseases. Most studies to date have associative in nature, meaning that epigenetic differences are correlated with the occurrence, or particular phenotypes, of immune mediated inflammatory disorders (IMIDs). That being said, at the level of histone modifications, there is some evidence that epigenetics may actually modulate the inflammatory phenotype through particular epigenetic readers and erasers. One of the biggest problems in understanding how epigenetics affects the pathogenesis and/or etiology is due to the fact that epigenetics is a cell-type specific feature with most studies interrogating heterogeneous populations: any “epigenetic” difference could be the result of population differences and/or actual differences at the level of the epigenome. This is exactly the question we try to elucidate in work package 5 where we seek to disentangle the DNA methylome from cellular heterogeneity.

Why is this research novel and does it add to existing techniques?

The current research is novel in that the use of DNA methylation as biomarker for predicting response to therapy has not been implemented outside the field of oncology. Beyond the DNA methylation analyses on peripheral blood, the characterization of DNA methylation on single cells is not an experiment that is done routinely. If successful, our data would not only show that the implementation is possible in peripheral blood, but also provide a resource for other researchers to interrogate the DNA methylome at single cell level.

What is an AI algorithm?

An AI algorithm can be a very broad term. The way we are implementing our algorithm is essentially a set of rules that define, based on the DNA methylome, whether the provided DNA methylation data from a particular sample resembles more a responder or non-responder. The AI algorithm is in our case a (set of) decision tree(s), which essentially boils down the same principle used by daycares in the Netherlands during COVID-19 when deciding whether a could go to the daycare. Importantly, the actual AI algorithm does not need to be the most complicated (although it can certainly be!) but rather the process by which one arrives at such an algorithm. This process is, just like the rest of science, an iterative process by which the most optimal algorithm is decided upon through multiple rounds of training and validation.

Three questions for Luisa Avedano, EFCCA Chief Executive Officer

1 What is your motivation to participate in this project?

My motivation is not an individual one but it represents the collective view of EFCCA, the organisation I work for. Being a second-level patient association our main motivation is to be part of cutting-edge research aimed at advancing the understanding of the disease and in particular predicting the response of some specific biological treatments, that can lead to the development of new approaches to therapy, and understanding of the disease. By sharing a patient perspective to this high-level research project we hope to play a role in identifying more effective treatments or strategies for managing the disease more effectively. We also hope to contribute to addressing unmet needs in IBD, in particular to finding solutions for challenges in IBD care, treatment, and quality of life.

2 What do you think is the biggest challenge in this project?

Identifying more personalised treatments for the targeted diseases (Crohn’s Disease, Psoriasis and Reumathoid Arthritis) and thus contributing to improving patients’ quality of life and care in the long term. This aspect is particularly important from the patient perspective.

3 What do you hope this research will bring to the lives of patients with Crohn’s disease?

A more articulated knowledge of some aspects of the disease to achieve a better treatment response and improve the quality of life of Crohn’s Disease patients.

Patients' questions about METHYLOMIC

This is considered personalized medicine. What exactly is that?

Wouter de Jonge, professor of Experimental Gastroenterology, Amsterdam UMC:

Personalized medicine is an approach based on the fact that each patient is different and therefore needs their own personal treatment. There is no one-size-fits-all solution that will work for everybody. Instead, it focuses on customizing medical care to meet the unique needs of each individual, ultimately improving the effectiveness and safety of medical therapy. Personalized medicine takes into account various elements, including a patient’s genetic code, lifestyle, environment, and personal health history. By carefully analyzing these factors, healthcare providers can make more informed decisions about therapeutic options.

Patients' questions about METHYLOMIC

What exactly are you going to do in this study?

Wouter de Jonge, professor of Experimental Gastroenterology, Amsterdam UMC:

This study is a significant step forward in personalized medicine, where we aim to offer more targeted and effective treatments based on the unique characteristics of each patient.
Presently, there are many different options to treat Crohn’s Disease patients with medication, but these help only part of the patients. It sometimes takes months or even years before doctors and patients know if a certain treatment with medications is effective or not. It would be great to know upfront which medication will help and which will not. Or whether a patient needs surgery or can be helped with medication.
We developed a blood test based on epigenetics in blood cell DNA. We tested it on 360 patients with Crohn’s Disease, with very promising results. Now we are going to find out in a patient trial if such a blood test enables us to know which medication should be used for which patient with Crohn’s Disease. This will be done in the OmiCrohn trial. The patients that will participate in this trial will be divided into two groups. One group will receive a treatment based on the epigenetic profile, from the blood test. The other group will receive regular treatment, based on standard care. As soon as treatment starts, we will closely monitor the effectiveness of the chosen therapies. Patients will receive regular medical assessments, including colonoscopies, ultrasounds, and multiple blood tests. By comparing the two patient groups the researchers will be able to determine if choosing a treatment based on the epigenetic biomarker is a good option. In essence, we are trying to understand if these biomarkers can serve as reliable guides in choosing treatments for Crohn’s Disease patients.

Three questions for Wouter de Jonge, professor of Experimental Gastroenterology, Amsterdam UMC

1 What is your motivation to participate in this project?

I am interested in the biology of the intestine, and how the bacteria, neurons and other cells and immune systems all work in harmony. I am also motivated to help and solve clinical problems. Crohn’s Disease is an example of a disease that is difficult to explain as it seems like a perfect storm that leads to disease without a clear course. Each patient is different from another. For instance, why are lesions so local, and why is the course and tissue involved always so unpredictable? However, it seemed to me like a devastating disease to have, with sometimes a lot of suffering and little perspective. From a pharmacological perspective the current way to treat patients doesn’t seem to lead to a good solution for everybody. Thus, the strategy for treatment could be improved. With this project, I felt we have a perfect mix of ideas and people to solve this problem. I am also interested in how epigenetics works. As this project also studies this, this is also what motivates me.

2 What do you think is the biggest challenge in this project?

The biggest challenge is to recruit enough patients. And also, to find out whether the design of the study is good enough to show the effect we wish to see, namely that treatment has improved. Some of the biological questions, about the fundamental role of the epigenetic biomarkers, are going to be a challenge. But greatly interesting ones with a high reward, if we get it done.

3 What do you hope this research will bring to the lives of patients with Crohn’s disease?

I hope we can come to a better and more effective treatment, with less complications and side effects. I also hope that new medication can be better tested with our method. Also, I hope our method works in other diseases with even more patients such as Rheumatoid Arthritis and Psoriasis, and maybe even for instance dementia. If this methodology works, the sky is the limit in how important it can be for healthcare.

Webinar on progress METHYLOMIC Project

 

The METHYLOMIC project aims to implement epigenetic blood tests to help physicians determine the most optimal treatment for each Crohn’s disease patient. We will be doing a prospective trial in almost 400 patients.

Prof. dr. Wouter de Jonge and Andrew Yi Lim talked about the progress on this project in a webinar on July 5th, organised by our partner GenDx.

The consortium comprises eighteen participants consisting of clinical, epigenetic, and DNA diagnostics experts, patient organizations, and companies across nine countries to ensure effective communication and commitment to help ease the challenges of patients with Crohn’s disease, Rhematoid Arthritis and Psoriasis.

Attendances of the webinar received 0.15 continuing education credits (CECs).

View the webinar