Periodic Reporting for period 3 - TAXINOMISIS (A multidisciplinary approach for the stratification of patients with carotid artery disease)
Okres sprawozdawczy: 2021-01-01 do 2022-06-30
Carotid artery disease, the primary trigger of ischaemic cerebrovascular events including stroke, causes major morbidity, mortality and healthcare costs worldwide. Still, treatment is based on criteria established in the 90s that do not take into account the molecular evolution we have witnessed since, nor the introduction of new medication, leading to remarkably high unnecessary surgical treatment while missing most patients at risk. TAXINOMISIS will provide novel disease mechanism-based stratification for carotid artery disease patients to address the needs for stratified and personalised therapeutic interventions in the current era. TAXINOMISIS will deliver, as a main outcome, a software platform, which can perform the risk stratification.
TAXINOMISIS has the following six objectives:
-To characterize the mechanisms mediating carotid artery disease in the present era and current patient domain, and identify susceptibility and protection factors of plaque symptomatology through the exploitation of longitudinal cohorts and biobanks, deep cell profiling and multi-omics of carotid atherosclerosis.
-To apply systems biomedicine approaches, in order to define distinct disease endotypes and generate molecular fingerprints of high versus low risk states encompassing existing and novel circulatory biomarkers, to assist patient stratification and disease prognosis.
-To integrate computational multilevel models with agent based models and develop a risk stratification tool, to assist patient stratification and clinical decision making.
-To develop novel pharmacogenomics solutions for carotid artery disease based on an innovative lab-on-a-chip technology to refine patient stratification and support personalized medical treatment.
-To evaluate the effectiveness of the new risk stratification model and the lab-on-a-chip device in an international multicentre clinical study setting.
-To assess the commercialization opportunities through cost effectiveness analysis and review of the ethical and regulatory implications of the new risk stratification tool versus the current practices and guidelines.
The benefits for the society are:
- The establishment of new computational models for patient stratification to assist clinical decision-making.
- The acceleration of the biomedical and clinical research results to medical use.
- The improved cost-effectiveness of the new approach compared to established clinical practices.
- The new research and innovation opportunities for small or medium-sized enterprises.
TAXINOMISIS project officially started as of 1st of January 2018. The consortium consists of 16 partners from 10 countries.
TAXINOMISIS has the following six objectives:
-To characterize the mechanisms mediating carotid artery disease in the present era and current patient domain, and identify susceptibility and protection factors of plaque symptomatology through the exploitation of longitudinal cohorts and biobanks, deep cell profiling and multi-omics of carotid atherosclerosis.
-To apply systems biomedicine approaches, in order to define distinct disease endotypes and generate molecular fingerprints of high versus low risk states encompassing existing and novel circulatory biomarkers, to assist patient stratification and disease prognosis.
-To integrate computational multilevel models with agent based models and develop a risk stratification tool, to assist patient stratification and clinical decision making.
-To develop novel pharmacogenomics solutions for carotid artery disease based on an innovative lab-on-a-chip technology to refine patient stratification and support personalized medical treatment.
-To evaluate the effectiveness of the new risk stratification model and the lab-on-a-chip device in an international multicentre clinical study setting.
-To assess the commercialization opportunities through cost effectiveness analysis and review of the ethical and regulatory implications of the new risk stratification tool versus the current practices and guidelines.
The benefits for the society are:
- The establishment of new computational models for patient stratification to assist clinical decision-making.
- The acceleration of the biomedical and clinical research results to medical use.
- The improved cost-effectiveness of the new approach compared to established clinical practices.
- The new research and innovation opportunities for small or medium-sized enterprises.
TAXINOMISIS project officially started as of 1st of January 2018. The consortium consists of 16 partners from 10 countries.
WP1:
-We generated data from CD45+ cells collected from carotid endarterectomies of symptomatic and asymptomatic patients using both CYTOF and scRNAseq technologies.
-Our cellular atlas maps the biology of vascular immune cells in human atherosclerosis and its transcriptional alterations linked to plaque vulnerability.
-Our data distinguish homeostatic from pathogenic immune cell in human atherosclerosis with broad implications for the design of safer drugs for CVD.
WP2 (completed in RP2):
-Five new Endotypes of carotid artery disease were defined by clustering atherosclerotic plaque and plasma patient samples into biologically and clinically relevant disease subtypes: Fibrous (Endotype 1), Inflammatory (Endotype 2), Lipo-necrotic (Endotype 3), Fibro-inflammatory (Endotype 4), and Fibro-productive (Endotype 5)
-Endotypes 3 and 4 are associated with higher risk states, Endotype 2 with intermediate risk states and Endotypes 5 and 1 with lower risk states
-The five new Endotypes were clustered based on unsupervised gene expression analysis, pathway analysis and histological characterization and were further associated with the presence of symptoms, plaque instability, circulating biomarkers and clinical characteristics
WP3:
-The TAXINOMISIS contribution to improve the Standard of Care has been defined as a 3 level approach and it has been approved by the 6 clinical centers which participate in the project
- All the individual modules of the risk stratification tool have been further developed and the validation process is in progress following the data availability from the follow-up visits in the prospective clinical study
- The computational model of plaque progression has been further extended to incorporate new knowledge from WP1-WP2
- A first version of the risk stratification platform has been developed integrating gradually all the individual modules
- A first user manual has been also created
WP4:
-Successful experiments have shown the technical validation of the lab-on-chip solution from an engineering perspective as proposed in the project
-2 SNP assays were used for this validation that were spotted in alternating cavities on the multicavity chip
-Further optimization of the clamp solution was performed to allow for improved reproducibility and user-friendliness
-A more thorough biochemical optimization of the selected assays on chip will be needed to ensure optimal sensitivity and specificity and decreased time to result to unlock the entire potential of IMEC’s multicavity chip
WP5:
-Clinical trial protocol
-Protocol submission in www.clinicaltrials.gov (study ID: NCT03495830)
-Ethical Approval obtained
-345 patients recruited
-electronic Case Report Form developed
-The concept of the Risk stratification tool has been accepted among the clinical partners. Four unresolved areas in the current standard of care have been selected
-The follow-up progress has been monitored with conference calls with clinical partners
WP6:
-Clinical centers monitored by ESCVS
-Ethical and Legal issues addressed by the clinical study protocol
-The regulatory strategy planning has been presented
-The cost effectiveness and commercialization opportunities analyses, as well as the current regulatory and ethical framework review have been taking place in parallel with the clinical study, in order to achieve adoption of the TAXINOMISIS exploitable products.
WP7:
-Communication and dissemination activities (v2)
-Exploitation and innovation plan (v2)
-We generated data from CD45+ cells collected from carotid endarterectomies of symptomatic and asymptomatic patients using both CYTOF and scRNAseq technologies.
-Our cellular atlas maps the biology of vascular immune cells in human atherosclerosis and its transcriptional alterations linked to plaque vulnerability.
-Our data distinguish homeostatic from pathogenic immune cell in human atherosclerosis with broad implications for the design of safer drugs for CVD.
WP2 (completed in RP2):
-Five new Endotypes of carotid artery disease were defined by clustering atherosclerotic plaque and plasma patient samples into biologically and clinically relevant disease subtypes: Fibrous (Endotype 1), Inflammatory (Endotype 2), Lipo-necrotic (Endotype 3), Fibro-inflammatory (Endotype 4), and Fibro-productive (Endotype 5)
-Endotypes 3 and 4 are associated with higher risk states, Endotype 2 with intermediate risk states and Endotypes 5 and 1 with lower risk states
-The five new Endotypes were clustered based on unsupervised gene expression analysis, pathway analysis and histological characterization and were further associated with the presence of symptoms, plaque instability, circulating biomarkers and clinical characteristics
WP3:
-The TAXINOMISIS contribution to improve the Standard of Care has been defined as a 3 level approach and it has been approved by the 6 clinical centers which participate in the project
- All the individual modules of the risk stratification tool have been further developed and the validation process is in progress following the data availability from the follow-up visits in the prospective clinical study
- The computational model of plaque progression has been further extended to incorporate new knowledge from WP1-WP2
- A first version of the risk stratification platform has been developed integrating gradually all the individual modules
- A first user manual has been also created
WP4:
-Successful experiments have shown the technical validation of the lab-on-chip solution from an engineering perspective as proposed in the project
-2 SNP assays were used for this validation that were spotted in alternating cavities on the multicavity chip
-Further optimization of the clamp solution was performed to allow for improved reproducibility and user-friendliness
-A more thorough biochemical optimization of the selected assays on chip will be needed to ensure optimal sensitivity and specificity and decreased time to result to unlock the entire potential of IMEC’s multicavity chip
WP5:
-Clinical trial protocol
-Protocol submission in www.clinicaltrials.gov (study ID: NCT03495830)
-Ethical Approval obtained
-345 patients recruited
-electronic Case Report Form developed
-The concept of the Risk stratification tool has been accepted among the clinical partners. Four unresolved areas in the current standard of care have been selected
-The follow-up progress has been monitored with conference calls with clinical partners
WP6:
-Clinical centers monitored by ESCVS
-Ethical and Legal issues addressed by the clinical study protocol
-The regulatory strategy planning has been presented
-The cost effectiveness and commercialization opportunities analyses, as well as the current regulatory and ethical framework review have been taking place in parallel with the clinical study, in order to achieve adoption of the TAXINOMISIS exploitable products.
WP7:
-Communication and dissemination activities (v2)
-Exploitation and innovation plan (v2)
TAXINOMISIS solution has innovative and distinctive characteristics which rely on the ability to stratify vulnerable plaques based on the information collected from a large population of carotid artery disease patients. Within RP2, the conceptual framework of the Risk Stratification Tool has been defined and four unresolved areas in the current standard of care have been selected in which TAXINOMISIS can contribute to improve risk stratification and management of carotid artery disease patients. By improving the current standard of care the socio-economic impact of the project and the wider societal benefit will be significant.
The business model supports the way in which TAXINOMISIS software platform can be proposed to the market and it is built on three distinctive factors which are:
• A tool to profile the patient’s plaque phenotypes and endotypes that will be implemented through state-of-the-art computational and mathematical models and algorithms
• A data stratification tool to stratify the patients according to their disease risk
• A lab-on-a-chip tool to improve risk stratification of patients through pharmacogenomics
The business model supports the way in which TAXINOMISIS software platform can be proposed to the market and it is built on three distinctive factors which are:
• A tool to profile the patient’s plaque phenotypes and endotypes that will be implemented through state-of-the-art computational and mathematical models and algorithms
• A data stratification tool to stratify the patients according to their disease risk
• A lab-on-a-chip tool to improve risk stratification of patients through pharmacogenomics