Periodic Reporting for period 3 - DocTIS (DECISION ON OPTIMAL COMBINATORIAL THERAPIES IN IMIDS USING SYSTEMS APPROACHES)
Berichtszeitraum: 2023-01-01 bis 2024-06-30
Immune-Mediated Inflammatory Diseases (IMIDs) are a group of common autoimmune diseases that include clinically heterogeneous disorders such as rheumatoid arthritis, psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis and systemic lupus erythematosus. Despite their clinical heterogeneity, IMIDs share a significant number of features at the molecular and cellular levels. Recently developed therapies like anti-TNF agents, targeting common key molecules of the immune system, have collectively resulted in a significant improvement in the management of IMIDs. Despite this major medical achievement, there is a still a too high percentage of patients who will not respond at all to a given targeted therapy (40% on average). Also, none of the developed therapies are able to achieve complete remission for most patients or for a sustained amount of time. This lack of efficacy affects the quality of life of many patients and poses an enormous social and economic burden.
The DocTIS project is aimed at addressing the urgent need to discover effective therapeutic strategies for IMIDs in a personalised way. It proposes using novel systems level approaches to identify the best drug combinations based on translating the data from high-throughput technology analysis of biobank samples from patients, highly curated clinical data, and evidence from model organisms into actionable evidence to on which to base preclinical studies of combinatorial therapies.The main objective of the project is to provide a clinical proof of concept that a deep understanding of the pathophysiology of IMIDs can be used to find synergic treatments that will be much more beneficial than the current monotherapy approach.
The DocTIS project is aimed at addressing the urgent need to discover effective therapeutic strategies for IMIDs in a personalised way. It proposes using novel systems level approaches to identify the best drug combinations based on translating the data from high-throughput technology analysis of biobank samples from patients, highly curated clinical data, and evidence from model organisms into actionable evidence to on which to base preclinical studies of combinatorial therapies.The main objective of the project is to provide a clinical proof of concept that a deep understanding of the pathophysiology of IMIDs can be used to find synergic treatments that will be much more beneficial than the current monotherapy approach.
The following work has been performed:
Regarding WP2, High throughput data management, the clinical database was recoded into international standard annotations in order to fulfil the FAIR recommendations (i.e. SNOMED-CT and WHO terminologies). The DoCTIS data analysis environment -JupyterLab Notebook- was created in the IMIDomics EC2 cloud server, and is ready to undergo the computational analyses required for the processing and analysis of the molecular and clinical data associated with the project.
Regarding WP3, the selection from each of the 11 IMID x drug patient groups has been completed by CHARITÉ, UVERONA, UCARDIFF and VHIR. From this selection of patients, biological samples have been analyzed by partners CNAG and HAI (WP4) using different technologies including, genome-wide genotyping, blood RNA sequencing, single cell PBMC transcriptomics and plasma proteomics.
In WP5, Systems biology analysis, VHIR and IMIDomics have co-developed the Mitigation of Non-Response Signature (MNRS) using bulk transcriptomics data from the analyzed patients. The MNRS is the central analytical approach followed in DoCTIS. It works by identifying the complementarity between drug effects on neutralizing the disease activity. The resulting strategy has successfully identified pairs of drugs that are complementary on each particular disease. These strongest combinatorial therapies have been evaluated in the corresponding animal models develop in WP6. Previously, WP6 (led by IDIBAPS) has been developing the animal models for all 6 IMIDs and treated them with the corresponding monotherapies, to obtain the reference therapeutic and safety effect.
Based on this evidence a selection of drug combinations has been finally selected and are currently being evaluated in clinical trial (WP8), led by UCARDIFF. Candidate biomarkers for patient stratification for combination therapies have been identified by IMIDomics (WP7) and will be evaluated with clinical trial cohort.
Regarding WP9, Dissemination and exploitation, new publications have been published based on DoCTIS, including scientific manuscripts and relevant news from the participating partners and recent developments in IMIDs. These are all accessible to the international audience via the webpage (www.doctis.eu) and the Linkedin and X accounts.
Regarding WP2, High throughput data management, the clinical database was recoded into international standard annotations in order to fulfil the FAIR recommendations (i.e. SNOMED-CT and WHO terminologies). The DoCTIS data analysis environment -JupyterLab Notebook- was created in the IMIDomics EC2 cloud server, and is ready to undergo the computational analyses required for the processing and analysis of the molecular and clinical data associated with the project.
Regarding WP3, the selection from each of the 11 IMID x drug patient groups has been completed by CHARITÉ, UVERONA, UCARDIFF and VHIR. From this selection of patients, biological samples have been analyzed by partners CNAG and HAI (WP4) using different technologies including, genome-wide genotyping, blood RNA sequencing, single cell PBMC transcriptomics and plasma proteomics.
In WP5, Systems biology analysis, VHIR and IMIDomics have co-developed the Mitigation of Non-Response Signature (MNRS) using bulk transcriptomics data from the analyzed patients. The MNRS is the central analytical approach followed in DoCTIS. It works by identifying the complementarity between drug effects on neutralizing the disease activity. The resulting strategy has successfully identified pairs of drugs that are complementary on each particular disease. These strongest combinatorial therapies have been evaluated in the corresponding animal models develop in WP6. Previously, WP6 (led by IDIBAPS) has been developing the animal models for all 6 IMIDs and treated them with the corresponding monotherapies, to obtain the reference therapeutic and safety effect.
Based on this evidence a selection of drug combinations has been finally selected and are currently being evaluated in clinical trial (WP8), led by UCARDIFF. Candidate biomarkers for patient stratification for combination therapies have been identified by IMIDomics (WP7) and will be evaluated with clinical trial cohort.
Regarding WP9, Dissemination and exploitation, new publications have been published based on DoCTIS, including scientific manuscripts and relevant news from the participating partners and recent developments in IMIDs. These are all accessible to the international audience via the webpage (www.doctis.eu) and the Linkedin and X accounts.
The DocTIS will suppose an advance regarding the state of the art in the following areas:
- Combinatorial therapies in IMIDs: currently, patients suffering from IMIDs are treated with advanced therapies in the form of monotherapy. While some patients respond to these targeted therapies, many other do not. Even in those responding, efficacy is lost after some time. A strategy that has worked in other complex diseases, mainly in cancer, is to combine existing therapies for increased efficacy. The DoCTIS aims to achieve a similar success in the area of autoimmunity whereby the objective will be a strong and sustained control of inflammation in patients.
- Molecular data generation: previous studies analyzing drug response in IMIDs have mostly been based on bulk data analysis approaches. However, this approach misses critical biological information, like the complex cell population heterogeneity and specific functional states of the immune system. To provide the information at the cell level, DoCTIS will apply single cell RNA-Seq technology to the samples of IMID patients. Profiling complex samples using scRNA-Seq will provide an invaluable complement to the bulk technologies that will be also used in the project. This multi-omic approach will generate a deep characterization of the biological processes associated with the response to targeted therapies in IMIDs.
- Systems biology analysis: DocTIS aims to show that the MNRS is a powerful framework with which to identify powerful combinations of therapies that work synergistically to reduce inflammation. DocTIS also aims to show that this approach could contributing to accelerate the clinical translation of research in types of pathologies other than the six IMIDs considered in this project.
- Personalised therapy biomarker development: at present, there is no companion diagnostic for any of the targeted therapies used in IMID patients. DocTIS aims to provide the European health systems with the first biomarker test that provides treatment personalization in IMIDs. With the companion diagnostic method developed at DocTIS, the clinical specialist will have an objective and reliable tool to identify the patients that will benefit most from the combinatorial drug therapy and, ultimately, increase the percentage of IMID patients in Europe that are under stable remission.
- Pre-clinical validation: DocTIS will test, both individually and in combination, the therapeutic efficacy and toxicological effects of the targeted therapies that are currently being used to treat IMID in a series of animal models of chronic autoimmune inflammation. This approach will enable head-to-head comparisons of these different compounds and their combinations in individual pathologies as well as across pathologies.
- Combinatorial therapies in IMIDs: currently, patients suffering from IMIDs are treated with advanced therapies in the form of monotherapy. While some patients respond to these targeted therapies, many other do not. Even in those responding, efficacy is lost after some time. A strategy that has worked in other complex diseases, mainly in cancer, is to combine existing therapies for increased efficacy. The DoCTIS aims to achieve a similar success in the area of autoimmunity whereby the objective will be a strong and sustained control of inflammation in patients.
- Molecular data generation: previous studies analyzing drug response in IMIDs have mostly been based on bulk data analysis approaches. However, this approach misses critical biological information, like the complex cell population heterogeneity and specific functional states of the immune system. To provide the information at the cell level, DoCTIS will apply single cell RNA-Seq technology to the samples of IMID patients. Profiling complex samples using scRNA-Seq will provide an invaluable complement to the bulk technologies that will be also used in the project. This multi-omic approach will generate a deep characterization of the biological processes associated with the response to targeted therapies in IMIDs.
- Systems biology analysis: DocTIS aims to show that the MNRS is a powerful framework with which to identify powerful combinations of therapies that work synergistically to reduce inflammation. DocTIS also aims to show that this approach could contributing to accelerate the clinical translation of research in types of pathologies other than the six IMIDs considered in this project.
- Personalised therapy biomarker development: at present, there is no companion diagnostic for any of the targeted therapies used in IMID patients. DocTIS aims to provide the European health systems with the first biomarker test that provides treatment personalization in IMIDs. With the companion diagnostic method developed at DocTIS, the clinical specialist will have an objective and reliable tool to identify the patients that will benefit most from the combinatorial drug therapy and, ultimately, increase the percentage of IMID patients in Europe that are under stable remission.
- Pre-clinical validation: DocTIS will test, both individually and in combination, the therapeutic efficacy and toxicological effects of the targeted therapies that are currently being used to treat IMID in a series of animal models of chronic autoimmune inflammation. This approach will enable head-to-head comparisons of these different compounds and their combinations in individual pathologies as well as across pathologies.