Periodic Reporting for period 3 - SILICOFCM (In Silico trials for drug tracing the effects of sarcomeric protein mutations leading to familial cardiomyopathy)
Berichtszeitraum: 2020-10-01 bis 2022-02-28
SILICOFCM project is funded from the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No 777204). The consortium consists of 14 partners representing universities, institutes, clinics and SMEs from 6 EU countries (The United Kingdom, Germany, Italy, Spain, Slovenia, Greece), 1 associated (Serbia) and 1 third country (USA).
SILICOFCM has developed a cloud-based computational platform for in silico clinical trials of Familial cardiomyopathies (FCMs) that takes into consideration comprehensive list of patient specific features (genetic, biological, pharmacologic, clinical, imaging and patient specific cellular aspects) capable of optimizing and testing medical treatment strategy with the purpose of maximizing positive therapeutic outcome, avoiding adverse effects, drug interactions, preventing sudden cardiac death, shortening time between the drug treatment commencement and the desired result.
SILICOFCM a multi-modular, innovative in silico clinical trial solution for design and functional optimization of whole heart performance and monitoring effectiveness of pharmacological treatment, with aim to reduce the animal studies and human clinical trials. The platform is based on the integrated multidisciplinary and multiscale methods for analysis of patient-specific data and development of patient-specific models for monitoring and assessment of patient condition from current through the progression of disease.
SILICOFCM has developed a cloud-based computational platform for in silico clinical trials of Familial cardiomyopathies (FCMs) that takes into consideration comprehensive list of patient specific features (genetic, biological, pharmacologic, clinical, imaging and patient specific cellular aspects) capable of optimizing and testing medical treatment strategy with the purpose of maximizing positive therapeutic outcome, avoiding adverse effects, drug interactions, preventing sudden cardiac death, shortening time between the drug treatment commencement and the desired result.
SILICOFCM a multi-modular, innovative in silico clinical trial solution for design and functional optimization of whole heart performance and monitoring effectiveness of pharmacological treatment, with aim to reduce the animal studies and human clinical trials. The platform is based on the integrated multidisciplinary and multiscale methods for analysis of patient-specific data and development of patient-specific models for monitoring and assessment of patient condition from current through the progression of disease.
In WP1, the Task 1.1 State-of-the-Art and Requirements Analysis, Task 1.2 SILICOFCM Specification and Task 1.3 SILICOFCM Reference Architecture are accomplished, contributing to design of the innovative SILICOFCM platform, tools and modules.
In WP2, the experiments for generation of physiological and biochemical data from human FCM samples and mouse models are accomplished, contributing also to the development and testing of computational models in WP5. The Task 2.1 Protein and cell data, Task 2.2 Physiological experiments and Task 2.3 Imaging acquisition data are completed.
In WP3, the retrospective clinical study (Task 3.1) is completed by integrating the anonymised HCM patients datasets from clinical partners, providing insight into cross-sectional demographic, clinical and genetic characteristics. The prospective clinical study (Task 3.2) aiming to evaluate the effect of pharmacological and lifestyle interventions on disease progression and clinical phenotype in HCM patients, and the genetic testing (Task 3.3) are completed, as well as the in vivo and ex vivo investigation of cardiomyopathies in rats (Task 3.4).
In WP4, a reference graph genome (Task 4.1) is created enabling rapid and accurate variant calling. Also, two bioinformatics pipelines for the analysis of the whole exome sequencing/targeted panel sequencing datasets are developed (Task 4.2) as well as the annotation of variant call sets (Task 4.3) called using the developed pipelines. This work contributed to the development of cardiomyopathy risk stratification system (Task 4.4).
In WP5, MUSICO platform is upgraded in order to trace the effect of the sarcomeric proteins mutations and precisely follow the implications of structural and kinetics changes of mutated proteins along multi-scales (Task 5.1) covering the data integration from different experimental setups. The upgraded FE biomechanical solvers PAK and Alya (Task 5.2) enable solving tightly coupled FS, electro-mechanic and ionic/drug transport simulations of the human heart. The linking of MUSICO and FE solvers (Task 5.4) has been followed by their continuous and parallel upgrades. The extraction of genetic data that serve as input to MUSICO simulations (Task 5.3) is accomplished.
In WP6, Development of virtual patients models repository (Task 6.1) Generation and visualization of virtual heart FCM cohorts (Task 6.2) and Predictive modelling using data mining algorithms (Task 6.3) are accomplished, developing the i) plausible virtual patients multi-repository for SILICOFCM tools, and ii) disease progression tool. The testing, evaluation, model validation and optimization are completed (Task 6.4).
In WP7, Integration in the cloud platform (Task 7.1) and Design and implementation of standard interconnection between systems (Task 7.2) are accomplished. The SILICOFCM platform is refined (Task 7.3) and MCDM tool has been integrated (Task 7.4).
In WP8, the activities related to Development workflow assistant for EMA/FDA approval (Task 8.1) Set up of R&D computation pipelines for drug testing (Task 8.2) Interface for drug database (Task 8.3) and Development of report tool (Task 8.4) are accomplished.
In WP9, successful dissemination and communication of project’s results through various channels attracted the identified stakeholders and raised awareness of SILICOFCM project. The exploitation plan is finalized, as well as the business plan for the project’s exploitable products.
In WP10, the administrative and financial management including quality control and DMP is accomplished.
In W11, the ethical requirements are followed though project lifetime
In WP2, the experiments for generation of physiological and biochemical data from human FCM samples and mouse models are accomplished, contributing also to the development and testing of computational models in WP5. The Task 2.1 Protein and cell data, Task 2.2 Physiological experiments and Task 2.3 Imaging acquisition data are completed.
In WP3, the retrospective clinical study (Task 3.1) is completed by integrating the anonymised HCM patients datasets from clinical partners, providing insight into cross-sectional demographic, clinical and genetic characteristics. The prospective clinical study (Task 3.2) aiming to evaluate the effect of pharmacological and lifestyle interventions on disease progression and clinical phenotype in HCM patients, and the genetic testing (Task 3.3) are completed, as well as the in vivo and ex vivo investigation of cardiomyopathies in rats (Task 3.4).
In WP4, a reference graph genome (Task 4.1) is created enabling rapid and accurate variant calling. Also, two bioinformatics pipelines for the analysis of the whole exome sequencing/targeted panel sequencing datasets are developed (Task 4.2) as well as the annotation of variant call sets (Task 4.3) called using the developed pipelines. This work contributed to the development of cardiomyopathy risk stratification system (Task 4.4).
In WP5, MUSICO platform is upgraded in order to trace the effect of the sarcomeric proteins mutations and precisely follow the implications of structural and kinetics changes of mutated proteins along multi-scales (Task 5.1) covering the data integration from different experimental setups. The upgraded FE biomechanical solvers PAK and Alya (Task 5.2) enable solving tightly coupled FS, electro-mechanic and ionic/drug transport simulations of the human heart. The linking of MUSICO and FE solvers (Task 5.4) has been followed by their continuous and parallel upgrades. The extraction of genetic data that serve as input to MUSICO simulations (Task 5.3) is accomplished.
In WP6, Development of virtual patients models repository (Task 6.1) Generation and visualization of virtual heart FCM cohorts (Task 6.2) and Predictive modelling using data mining algorithms (Task 6.3) are accomplished, developing the i) plausible virtual patients multi-repository for SILICOFCM tools, and ii) disease progression tool. The testing, evaluation, model validation and optimization are completed (Task 6.4).
In WP7, Integration in the cloud platform (Task 7.1) and Design and implementation of standard interconnection between systems (Task 7.2) are accomplished. The SILICOFCM platform is refined (Task 7.3) and MCDM tool has been integrated (Task 7.4).
In WP8, the activities related to Development workflow assistant for EMA/FDA approval (Task 8.1) Set up of R&D computation pipelines for drug testing (Task 8.2) Interface for drug database (Task 8.3) and Development of report tool (Task 8.4) are accomplished.
In WP9, successful dissemination and communication of project’s results through various channels attracted the identified stakeholders and raised awareness of SILICOFCM project. The exploitation plan is finalized, as well as the business plan for the project’s exploitable products.
In WP10, the administrative and financial management including quality control and DMP is accomplished.
In W11, the ethical requirements are followed though project lifetime
SILICOFCM has produced a wide range of beyond the SoA results. It produces breakthrough on the current market via: i) In silico clinical trials for existing and new drugs for cardiomyopathy disease, ii) Patient specific heart simulation using genetic, clinical and imaging data, and iii) Cardiomyopathy risk stratification of patients – Decision Support and Disease Progression Tool.
The completed clinical trial is the first one which evaluates application of the most recent HF medication i.e. sacubitril/valsartan and lifestyle interventions on disease progression and clinical phenotype in HCM. Beside the HCM, computational models can be related to the other types of FCM by incorporating the data from retrospective studies and repositories. Moreover, the SILICOFCM Bioinformatics tool for the first time exploited the graph genome paradigm to increase accuracy in FCM genetic testing and investigates the relevant genetic variants and their interactions that could impact the level of cardiomyopathy risk, while developed Data analytics tool identifies cardiomyopathy patients with a high risk of severe events such as sudden cardiac death or life-threatening arrhythmias, and estimates disease progression.
The 3D segmentation tool, Bioinformatics tool, MUSICO tool, MCDM tool, Data analytics tool and FE tools (Alya and PAK) are upgraded and integrated into the SILICOFCM platform, as well as the Virtual population and Virtual experiments databases. These are in direction of risk stratification, drug efficiency and cardiomyopathy disease progression. The end-users of platform - pharmaceutical companies, medical doctors and researchers, actively participated in refinement of SILICOFCM solutions.
The SILICOFCM platform integrates various tools, modules and engines following the reference architecture, functional and non-functional specifications and ISO standards. During the integration and refinement phase, the SILICOFCM tools are validated in representative scenarios (available at the project website) to demonstrate the efficacy of the in silico clinical trial platform which foresees significant maximization of positive therapeutic outcome and reduction of animal studies and human clinical trials. Finally, the SILICOFCM platform contributes to the liaison of in silico clinical trials and regulatory pathways aiming to raise its adoption in clinical practice.
The completed clinical trial is the first one which evaluates application of the most recent HF medication i.e. sacubitril/valsartan and lifestyle interventions on disease progression and clinical phenotype in HCM. Beside the HCM, computational models can be related to the other types of FCM by incorporating the data from retrospective studies and repositories. Moreover, the SILICOFCM Bioinformatics tool for the first time exploited the graph genome paradigm to increase accuracy in FCM genetic testing and investigates the relevant genetic variants and their interactions that could impact the level of cardiomyopathy risk, while developed Data analytics tool identifies cardiomyopathy patients with a high risk of severe events such as sudden cardiac death or life-threatening arrhythmias, and estimates disease progression.
The 3D segmentation tool, Bioinformatics tool, MUSICO tool, MCDM tool, Data analytics tool and FE tools (Alya and PAK) are upgraded and integrated into the SILICOFCM platform, as well as the Virtual population and Virtual experiments databases. These are in direction of risk stratification, drug efficiency and cardiomyopathy disease progression. The end-users of platform - pharmaceutical companies, medical doctors and researchers, actively participated in refinement of SILICOFCM solutions.
The SILICOFCM platform integrates various tools, modules and engines following the reference architecture, functional and non-functional specifications and ISO standards. During the integration and refinement phase, the SILICOFCM tools are validated in representative scenarios (available at the project website) to demonstrate the efficacy of the in silico clinical trial platform which foresees significant maximization of positive therapeutic outcome and reduction of animal studies and human clinical trials. Finally, the SILICOFCM platform contributes to the liaison of in silico clinical trials and regulatory pathways aiming to raise its adoption in clinical practice.