Periodic Reporting for period 1 - METHYLOMIC (DNA methylation markers to predict treatment success of biologicals in Crohn’s disease.)
Periodo di rendicontazione: 2023-01-01 al 2024-06-30
Monoclonal antibodies have revolutionized the treatment landscape for immune-mediated inflammatory diseases (IMIDs) such as Crohn’s disease (CD), rheumatoid arthritis (RA), and psoriasis (PsO). These biologic therapies, targeting key inflammatory pathways, offer hope to many patients. However, a critical challenge persists: the inability to predict which patients will respond to a specific biologic treatment. Less than 40% of patients experience a primary response to any given therapeutic, leading to treatment failures that result in disease complications, increased healthcare costs, and diminished quality of life. This unpredictability underscores the urgent need for validated predictive biomarkers to guide personalized medicine in IMIDs.
The METHYLOMIC project aims to address this challenge by leveraging epigenetic biomarkers, particularly DNA methylation profiles, to predict treatment response in patients with CD and potentially other IMIDs. Building on previous cohort studies, our research has identified and validated differential DNA methylation profiles in peripheral blood as biomarkers of response to three approved biologics in CD. These profiles have shown the potential to predict treatment response with up to 93% accuracy. METHYLOMIC is dedicated to translating these findings into clinical practice, advancing personalized treatment selection for CD and beyond. To achieve this, METHYLOMIC has brought together a consortium of clinical experts, epigenetic researchers, DNA diagnostics specialists, patient organizations, and industry partners across Europe. The project undertakes extensive clinical validation studies to ensure that our predictive algorithm-supported epigenetic biomarker assay meets the rigorous regulatory standards required for clinical approval. Additionally, we aim to develop a rapid, market-ready targeted methylation assay, which will be validated through a unique prospective randomized clinical trial for CD.
The ultimate goal of METHYLOMIC is to reduce the burden of Crohn’s disease by accelerating the clinical application of a predictive epigenetic biomarker assay. By enabling a more accurate selection of the most suitable biological therapy for individual patients, this assay is expected to significantly improve treatment outcomes, reduce healthcare costs, and enhance the quality of life for patients. METHYLOMIC’s impact extends beyond the immediate clinical benefits. By providing a validated tool for personalized medicine in CD, the project aligns with broader strategic goals of reducing the burden of chronic diseases, improving patient care, and making healthcare more efficient and cost-effective. The successful implementation of this assay in clinical practice could serve as a model for personalized treatment in other IMIDs, further amplifying its significance.
The METHYLOMIC project aims to address this challenge by leveraging epigenetic biomarkers, particularly DNA methylation profiles, to predict treatment response in patients with CD and potentially other IMIDs. Building on previous cohort studies, our research has identified and validated differential DNA methylation profiles in peripheral blood as biomarkers of response to three approved biologics in CD. These profiles have shown the potential to predict treatment response with up to 93% accuracy. METHYLOMIC is dedicated to translating these findings into clinical practice, advancing personalized treatment selection for CD and beyond. To achieve this, METHYLOMIC has brought together a consortium of clinical experts, epigenetic researchers, DNA diagnostics specialists, patient organizations, and industry partners across Europe. The project undertakes extensive clinical validation studies to ensure that our predictive algorithm-supported epigenetic biomarker assay meets the rigorous regulatory standards required for clinical approval. Additionally, we aim to develop a rapid, market-ready targeted methylation assay, which will be validated through a unique prospective randomized clinical trial for CD.
The ultimate goal of METHYLOMIC is to reduce the burden of Crohn’s disease by accelerating the clinical application of a predictive epigenetic biomarker assay. By enabling a more accurate selection of the most suitable biological therapy for individual patients, this assay is expected to significantly improve treatment outcomes, reduce healthcare costs, and enhance the quality of life for patients. METHYLOMIC’s impact extends beyond the immediate clinical benefits. By providing a validated tool for personalized medicine in CD, the project aligns with broader strategic goals of reducing the burden of chronic diseases, improving patient care, and making healthcare more efficient and cost-effective. The successful implementation of this assay in clinical practice could serve as a model for personalized treatment in other IMIDs, further amplifying its significance.
During the first period of the METHYLOMIC project, significant progress was made across multiple work packages, focusing on the technical and scientific objectives aimed at validating DNA methylation markers for personalized treatment in Crohn’s disease (CD), rheumatoid arthritis (RA), and psoriasis (PsO).
Bioinformatics and Algorithm Development (WP1):
The team successfully generated, improved, and refined the predictive algorithm used to determine patient response to biologic treatments in CD. Key achievements include the identification of critical CpG sites and the calibration of the algorithm using patient data from multiple cohorts. This work has laid the foundation for a robust predictive model that can be further validated in clinical settings.
Rapid NGS Targeted Methylation Assay Development (WP2):
A major milestone was the development and analytical validation of a rapid NGS-based targeted methylation assay. This assay is designed for use in the OMICROHN prospective clinical trial, aimed at predicting patient response to biologic therapies.
Prospective Clinical Trial Initiation (WP3):
Significant groundwork was completed for the OMICROHN clinical trial, including obtaining regulatory approvals across multiple countries and initiating site contracts. The trial aims to clinically validate the predictive power of the methylation assay in selecting the most effective biologic therapy for CD patients. Additionally, the team developed comprehensive electronic case report forms (eCRFs) and established a robust web-based randomization and clinical data management platform.
Extrapolation to Rheumatoid Arthritis and Psoriasis (WP4):
The project also advanced in preparing for the prospective sampling study EPISORA, which will validate the use of DNA methylation markers for predicting therapy success in RA and PsO patients. Key achievements include the development of study protocols, the finalization of ethical approvals, and the establishment of sample collection frameworks.
Single-Cell DNA Methylomics (WP5):
To deepen the understanding of therapy response at the cellular level, the team optimized protocols for isolating and analyzing peripheral blood mononuclear (PBMCs) and polymorphonuclear (PMNs) leukocytes. A pilot study was initiated to assess the technical feasibility of the smart-RRBS protocol, which combines methylome and transcriptome analysis at the single-cell level.
Overall, the METHYLOMIC project has made substantial progress toward its technical and scientific goals. Each work package has successfully initiated its key activities, laying a solid foundation for the continued development and validation of personalized treatment strategies for chronic inflammatory diseases.
Bioinformatics and Algorithm Development (WP1):
The team successfully generated, improved, and refined the predictive algorithm used to determine patient response to biologic treatments in CD. Key achievements include the identification of critical CpG sites and the calibration of the algorithm using patient data from multiple cohorts. This work has laid the foundation for a robust predictive model that can be further validated in clinical settings.
Rapid NGS Targeted Methylation Assay Development (WP2):
A major milestone was the development and analytical validation of a rapid NGS-based targeted methylation assay. This assay is designed for use in the OMICROHN prospective clinical trial, aimed at predicting patient response to biologic therapies.
Prospective Clinical Trial Initiation (WP3):
Significant groundwork was completed for the OMICROHN clinical trial, including obtaining regulatory approvals across multiple countries and initiating site contracts. The trial aims to clinically validate the predictive power of the methylation assay in selecting the most effective biologic therapy for CD patients. Additionally, the team developed comprehensive electronic case report forms (eCRFs) and established a robust web-based randomization and clinical data management platform.
Extrapolation to Rheumatoid Arthritis and Psoriasis (WP4):
The project also advanced in preparing for the prospective sampling study EPISORA, which will validate the use of DNA methylation markers for predicting therapy success in RA and PsO patients. Key achievements include the development of study protocols, the finalization of ethical approvals, and the establishment of sample collection frameworks.
Single-Cell DNA Methylomics (WP5):
To deepen the understanding of therapy response at the cellular level, the team optimized protocols for isolating and analyzing peripheral blood mononuclear (PBMCs) and polymorphonuclear (PMNs) leukocytes. A pilot study was initiated to assess the technical feasibility of the smart-RRBS protocol, which combines methylome and transcriptome analysis at the single-cell level.
Overall, the METHYLOMIC project has made substantial progress toward its technical and scientific goals. Each work package has successfully initiated its key activities, laying a solid foundation for the continued development and validation of personalized treatment strategies for chronic inflammatory diseases.
There is no relevant published results generated yet at this stage of the Project.