LONG-TERM VISION
The project aims to revolutionize our understanding of ECs as active immune regulators (IMECs) and to exploit this knowledge for the development of innovative vascular-targeted therapies. By uncovering the immunomodulatory roles of mystery genes expressed by ECs in disease, the project lays the foundation for new therapeutic strategies in cancer, diabetes, and inflammatory disorders - diseases that affect hundreds of millions globally.
WORK PERFORMED
We developed new AI/ML tools to identify and prioritize immunosuppressive and immunostimulatory genes (e.g. AI4TargetDicovery-v1.0 scMystYdentifier-v2.0 GenePrior-v2.0 DL4CPath). To discover novel EC phenotypes and standardize the nomenclature of EC phenotypes, a human mega single-EC atlas (SCVASCAT) was created by integrating published sc- and snRNA-seq datasets across healthy & disease conditions (covering most organs and including a number of diseases). Using stringent criteria, we identified core EC-subtype markers conserved in disease and highlighted tissue-specific signatures. We conducted a comparative analysis of tumor- and peri-tumor-derived ECs from matched samples, and observed consistent changes across tumors, highlighting a pro-angiogenic and immune-modulatory phenotype (Veys K, Cell Reports, in revision).
Using these, we prioritized ~60 high-potential mystery genes with predicted immunoregulatory functions. To validate these targets, we designed a novel endothelial-specific lipid nanoparticle (LNP) platform enabling in vivo gene silencing. By incorporating siRNAs targeting the mystery gene, we can very cheaply (<€100/mouse) and quickly (<24 hours) silence the expression of our mystery genes in ECs in vivo – compared to €10K- €50K and 1-5 years to create a conditional knockout mouse. More than half of the prioritized targets showed therapeutic benefit in preclinical models (>50% lung tumor growth inhibition).
After selecting targets with sufficient therapeutic effect, we use our in-house developed ‘gene prioritization’ tool to quickly gather multiple molecular features (3D structure, expression pattern, disease association, subcellular localization, etc.) of our targets.
MAIN ACHIEVEMENTS
• Developed and use of novel AI/ML tools for rapid immune target discovery.
• Created a new EC-selective LNP-siRNA delivery system for fast in vivo validation (in lung diseases).
• Discovered and validated ~30 novel immune-modulatory EC targets.
• Built technically demanding but highly translational ex vivo human disease models (e.g. perfused tumor-on-chip systems).
• Initiated generation of therapeutic nanobodies & monoclonal antibodies for top candidates.
NEXT STEPS
Continue high-throughput in vivo validation of remaining mystery genes and expand therapeutic screening using nanobodies & monoclonal antibodies. Concurrently, scaling up disease models and exploring patent and trademark protection to facilitate clinical translation and engage industrial partners.
