"From the knowledge generated by the DOCTIS project we hope to make a leap in the way IMID patients are treated, and improve the long-term quality of life of thousands of patients", DOCTIS coordinator
To promote the activities of the project, DOCTIS has begun a series of interviews with the scientists behind the work. We begin this series with an interview with the coordination team of the project: Dra. Sara Marsal, coordinator of the DOCTIS project and Head of Rheumatology Department in Vall d’Hebron Hospital Campus, Barcelona, Spain and Antonio Juliá, Head of Rheumatology Research Group in Vall d’Hebron Hospital Campus, Barcelona, Spain.
How did the idea of creating DOCTIS come about?
One of the main focuses of our research at the Rheumatology Research Group in Vall d’Hebron University Hospital has been to progress in the treatment in patients afflicted with Immune-Mediated Inflammatory Diseases (IMIDs). IMIDs are common chronic diseases that affect a large percentage of the World population. Biomedical research has been successful at identifying new drugs that are efficacious at controling the inflammatory damage. However, these drugs do not work in some patients and, in those were they do, they tend to lose efficacy over time. A possible way to overcome this problem is to find combinations of drugs that are more efficacious together than separately. Also, identifying the patients that are more suitable for this combinatorial therapies, would help many clinicians to make the right choice. This strategy has been already been used to treat cancer, but there is yet scant evidence within IMIDs. Funded by the Spanish Grant System, at the Vall d’Hebron Research Institute, we built in 2006 a biobank specialized in IMIDs. This biobank is stil active and, to date, it is one the largest biobanks in IMID. It is directed by Prof Sara Marsal and it is the result of the collaboration of more than 100 clinical researchers from all around Spain. Based on this unique resource, multiple discoveries have been performed like identifying new risk genes for disease susceptibility, genes associated to relevant phenotypes like disease severity or response to therapy, as well as other non-genetic findings like one of the earliest studies of the urine metabolite profiles in this group of diseases. Among the cohorts recruited by the IMID Consortium, there were longitudinal collections of patients strating treatment with late-generation drugs. In 2019, the H2020 call “Systems approaches for the discovery of combinatorial therapies for complex disorders” presented a unique opportunity with which to study these patient cohorts for a key objective to us. Based on this, we were very lucky to reunite a unique group of experts in key research areas including clinical research, clinical trials, animal models, systems biology, single cell, omic and drug development.
What are its objectives and purpose?
The main objective of the DoCTIS project is to identify new combinatorial therapies in IMIDs that can surpass the efficacies currently obtained by monotherapies. A first step is to understand the biological features associated with drug response. For this we are going to deeply characterize at the omic and single cell levels a selected group of responders and non responders to monotherapies available from the IMID Biobank. In parallel, we will study the effect of the therapies in the mouse models of the six types of IMIDs. Using advanced systems biology techniques we will determine the optimal combinatorial drug candidates. The safety and efficacy of these drug combinations will be first tested in the mouse model. Those therapies with the best evidence at the human and animal model levels will be subsequently tested in patients following an modern clinical trial approach. To help select the type most likely responsive to the combinatorial therapy, we will develop a molecular biomarker tool. In those IMIDs where the combinatorial drug is found to be significantly good, the biomarker will provide a very practical tool for clinicians to select patients for this new type of therapy. From the knowledge generated by the DoCTIS project we hope to make a leap in the way IMID patients are treated, and improve the long-term quality of life of thousands of patients.
What is the role of the coordinator?
The Vall Hebron Research Institute, host of the Rheumatology Research Group, is the coordinator of the DoCTIS project. The main role of the coordinator is to act as main representative of the DoCTIS consortium and look after for the correct development of the project according to the initial planification. This includes ensuring good communication between partners, communication with the EU Comission (through technical and financial reports), as well as dissemniation of the achievements the European society. The coordinator must follow up that the fundings provided by the H2020 EU programme are correctly distrubuted and used in the different tasks that compose the different work packages. During the development of the project multiple internal and external events and circumstances can affect the original planification. The coordinator needs to ensure that these situations are dealt with and, together with the Consortium members, look for solutions that can ensure that the main objective of the project is reached with the highest quality.
How has the pandemic affected the project?
The impact of COVID19 pandemic in our project has been substantial, affecting many levels.
Many of the collaborators of DoCTIS are clinical specialists. As such, in the most intense periods of pandemic, had to dedicate most of their time to provide support to deal with the huge numbers of COVID19 hospitalizations. All of the partners, including private sector partners like IMIDomics, shifted their current research work to contribute to provide more understanding of this virus pandemic, and search for potential therapies to prevent severe outcomes of the disease including death. This shift has also affected the recruitment of patients in the IMID-Biobank. At the first stages of the pandemic it was uncertain how immunomodulatory therapies, the therapies that we aim to combine, could affect the risk of patients to be more vulnerable to infection and severity. While it has been finally shown that the therapies used in IMIDs are safe vs COVID19, it is still an important factor that is weighted by many specialists. We have also faced a slowing in many aspects related to basic research, including the transport of reagents and biological materials related to molecular analysis and the development of animal models. Most of the periodic meetings have not been done in person, something that was unprecedented in previous H2020 projects. Fortunately, the enthusiasm of the DoCTIS collaborators has allowed the study to progress at good pace despite this many hurdles.
Have there been any deviations from the main idea of the project?
The concept of combining drugs to enhance efficacy has been fostered substantially these
last years. Particularly in gastroenterology, where the lack of efficacious therapies has drastically affected the outcomes of many patients. This way, many clinical trials have been started in the recent years that are evaluation the combinatorial effect of approved therapies in Crohn’s Disease and/or Ulcerative Colitis. At DoCTIS we have adapted to this development; it has been the case of Vedolizumab, a therapy aimed at blocking integrin molecules that home lymphocytes to the inflammed gut. Since there are already clinical trials evaluating the combination of Vedolizumab with other therapies in the two inflammatory bowel diseases, we found there was little to add from our research and therefore have decided to remove it from our list of therapy combinations. Instead, we have included a drug called Usekinumab that simultaneously blocks two cytokines (IL12 and IL23) signalling, which will offer many more untested drug combinations.
What has DOCTIS contributed to your research?
DoCTIS is helping our group have a deeper understading of the biological mechanisms that
influence why a patient responds or not to a given therapy. Characterizing the factors responsible for individual heterogeneity is the next frontier in biomedical research. By using the power of new analytical tools like single cell RNA Sequencing, Proteomics and Network Biology, we are at a good position to unveil such factors and, ultimately, lead us to determine new therapies that can be much more effective at reducing tissue inflammation and its harmful consequences.
For you, what is the best thing about working on a project like DOCTIS?
The best of working in a project like DoCTIS is the possibility to work with the top clinical and biology researchers in the IMID field towards an objective that can improve the life of millions of patients.