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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - SILICOFCM (In Silico trials for drug tracing the effects of sarcomeric protein mutations leading to familial cardiomyopathy)

Teaser

Summary

SILICOFCM project is funded from the European Unionâ€™s Horizon 2020 research and innovation programme under Grant Agreement No 777204. SILICOFCM 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 country (Serbia) and 1 third country (USA).
SILICOFCM aims to develop a computational platform for in silico clinical trials of Familial cardiomyopathies (FCMs) that would take 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, avoiding drug interactions, preventing sudden cardiac death, shortening time between the drug treatment commencement and the desired result.
It is a multi-modular, innovative in silico clinical trial solution for the design and functional optimization of whole heart performance and monitoring effectiveness of pharmacological treatment, with aim to reduce the animal studies and the human clinical trials. The SILICOFCM 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.

Work performed

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 have been accomplished. The collected and analysed SoA technologies, user and hardware requirements contributed to design of the innovative SILICOFCM Reference Architecture which integrates different SILICOFCM advance tools and functional modules.
In WP2, the experiments for generation of physiological and biochemical data from human FCM samples and mouse models are in progress. Those data are needed for the simulation models development and testing (WP5). The Task 2.1 Protein and cell data and Task 2.2 Physiological experiments are on-going, while Task 2.3 Imaging acquisition data has been completed.
In WP3, the retrospective clinical study (Task 3.1) has been accomplished by integrating the dataset with anonymized patient data providing insight into cross-sectional demographic, clinical and genetic characteristics of HCM patients from 4 clinical partners. The prospective clinical study (Task 3.2) aiming to evaluate the effect of pharmacological and lifestyle interventions on disease progression and clinical phenotype in patients with HCMs is in progress, as well as the genetic testing (Task 3.3).
In WP4, a reference graph genome (Task 4.1) that incorporates known pathogenic variants and identified variants from large-scale population genomics projects has been created enabling rapid and accurate variant calling. Also, two bioinformatics pipelines for the analysis of the whole exome sequencing/targeted panel sequencing datasets have been developed (Task 4.2). The annotation of variant call sets (Task 4.3) called using the developed pipelines is in progress. This work contributes also to the on-going development of cardiomyopathy risk stratification system (Task 4.4).
In WP5, MUSICO platform is upgraded in order to trace the effect of the mutations of sarcomeric proteins and refined to precisely follow the implications of structural and kinetics changes of mutated proteins along multiple scales (Task 5.1). The MUSICO platform covers integration of data from the different experimental setups. The methodology performed for FE biomechanical simulation upgrade (Task 5.2) enables solving tightly coupled FS, electro-mechanic and ionic/drug transport simulations of the human heart. Nevertheless, the linking of MUSICO and FE solvers (Task 5.4) will be followed by their continuous and parallel upgrades. Additionally, the extraction of genetic data that serve as input to MUSICO simulations (Task 5.3) is in progress.
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 in progress, aiming to develop the virtual patients multi-repository which will provide plausible patient-specific synthetic data to the developed SILICOFCM tools.
In WP7, Integration in the cloud platform (Task 7.1) and Design and implementation of standard interconnection between systems (Task 7.2) have started in parallel with main objective to build the unified cloud based SILICOFCM platform integrating all SILICOFCM tools and modules.
The WP8 has not started yet. However, an initial collection of requirements and standardization activities is being performed.
In WP9, dissemination and communication of projectâ€™s results through various channels, attracting the identified stakeholders and raising the awareness of SILICOFCM are on-going. The initial business plan for the projectâ€™s expected exploitable products has been established.
In WP10, the administrative and financial management including quality control is being performed.
In W11, the ethical approvals have been accomplished.

Final results

SILICOFCM has already produced and will produce a wide range of beyond the SoA results. In particular, the patient specific diagnostic tool which leads to personalised medicine is being developed. The on-going clinical trial is the first one which evaluates application of the most recent heart failure medication i.e. sacubitril/valsartan and lifestyle interventions on disease progression and clinical phenotype in HCM. Beside the HCM, computational models will be related to the other types of FCM by incorporating the data from retrospective studies and available repositories. Moreover, the SILICOFCM bioinformatics tools for the first time exploit the graph genome paradigm to increase accuracy in FCM genetic testing and the genetic risk stratification algorithm, utilizing heterogeneous data (clinical, genetic, and imaging data). Also, the relevant genetic variants and their interactions that could impact the level of cardiomyopathy risk are being investigated.
During the project the 3D segmentation tool, Bioinformatics tool, MUSICO tool and Data analytics tool will be developed. Also, FE solvers Alya and PAK will be updated for FCM. Virtual population and experiments database will be developed. All of these tools, solvers and repositories will be in direction of risk stratification, drug efficiency and cardiomyopathy disease progression. The identified end-users of SILICOFCM platform are pharmaceutical companies, medical doctors and researchers.
The reference architecture of the SILICOFCM platform has been already designed, by integrating the various SILICOFCM tools and modules and based on the identified functional and non-functional specifications and ISO standards. During the integration and refinement phase, the SILICOFCM tools will be validated in representative scenarios to demonstrate the efficacy of the in silico clinical trial platform which foresees to significantly maximize the positive therapeutic outcome and reduce the animal studies and human clinical trials. Finally, SILICOFCM platform will contribute to the liaison of in silico clinical trials approaches and regulatory pathways aiming to raise its adoption in clinical practice.