Periodic Reporting for period 1 - INSPIRE (INnovation in Safety Pharmacology for Integrated cardiovascular safety assessment to REduce adverse events and late stage drug attrition.)
Berichtszeitraum: 2020-01-01 bis 2021-12-31
The vision of INSPIRE is to extend the toolbox for preclinical safety evaluation by exploring novel technologies and by turning these into new products or services for improved evaluation of drug-induced cardiovascular toxicity. This way, INSPIRE will contribute to more efficiency in drug development and will protect patients from experiencing cardiovascular adverse events.
In addition, INSPIRE constitutes a highly stimulating, multidisciplinary and intersectoral training programme for 15 early-stage researchers (i.e. PhD students). Through a balanced combination of hands-on research training, intersectoral secondments, local courses and network-wide events INSPIRE will equip the future generation of safety pharmacology scientists with a wide range of scientific knowledge and professional skills.
The main activities and results achieved so far can be summarized as follows:
• Progress was made towards an optimized protocol for reproducible differentiation and maturation of human pluripotent cell (“human induced pluripotent stem cells, hiPSC”) into cardiomyocytes for safety evaluation.
• Development and validation of hiPSC cardiomyocyte-based assays (e.g. based on high-throughput imaging, contractility assessment and molecular markers) to evaluate structural and functional cardiovascular toxicity after (chronic) drug exposure.
• Comparison of different machine learning strategies to speed-up the analysis of large electrophysiology (MEA) datasets and to assess predictive value and computational cost.
• Development of novel hardware and software prototypes to enable simultaneous evaluation of cardiovascular physiology and behavioural treats in awake socially interacting animals. To this end, different strategies for tracking of animals (e.g. video capture or localisation technology) were evaluated and will be combined with algorithms for automated classification of behaviours.
• Prototype numerical models for in silico simulation of haemodynamics were delivered and are ready for further iteration based on real-life experimental inputs.
• Mass spectrometry imaging (MSI) has been applied to quantify drug-exposure in different organs (including the heart) and will be coupled with proteomics in upcoming work.
• New approaches for the evaluation of drug-induced haemodynamic changes have been explored such as arterial stiffness and local (blood)flow patterns.
• Moreover, research was initiated towards mechanisms of cardiovascular toxicity related to anti-cancer drugs, such as tyrosine kinase inhibitors and doxorubicin.
• Along the same line, biomarkers have been explored, both functional and molecular ones, to identify specific patient populations at risk of cardiovascular toxicity.
• Regular meetings fostered interaction between scientist from academia, pharma industry, technology vendors, as well as regulatory agencies. This unique setting has provided the early-stage researchers with invaluable insights and excellent opportunities to develop themselves.