Periodic Reporting for period 1 - PRAETORIAN (EuroPean Training NetwoRks to TArget DAMPs and NETs: novel apprOaches in pRecision SepsIs pAtieNt care)
Periodo di rendicontazione: 2024-01-01 al 2025-12-31
Sepsis remains one of the major challenges for societies worldwide, causing an estimated 7-9 million deaths every year. It is the leading cause of death at intensive care units in the EU. This high mortality persists because at present methods for timely diagnosis are lacking and no effective therapy is available. Therefore, there is a clear and urgent medical need to provide novel diagnostics and therapeutics for use in sepsis. The PRAETORIAN Doctoral Network has created a doctorate programme to deliver innovative training on preclinical and clinical science, business- and entrepreneurial aspects, intellectual properties and more, covering multiple aspects of the drug discovery and development process. This programme is unique as it will deliver a new generation of young scientists, each Doctoral Candidates (DCs), who will collaboratively work to develop novel approaches in precision sepsis patient care providing new diagnostics and therapeutics to answer to an urgent unmet clinical need. Recent insights have indicated a pivotal role for neutrophil activation and so-called damage associated patterns in the initiation and propagation of sepsis. However a comprehensive view on how these processes cause the onset of sepsis remains elusive and there is an urgent need to translate experimental findings into adequate diagnostic and therapeutic solutions. PRAETORIAN was designed to address this urgent need by bringing together specialists from academia and industry to shape a new generation of entrepreneurial scientists who have skills, expertise and knowhow to further our understanding of sepsis pathophysiology into tangible and effective solutions for novel diagnosis and therapy.
WP1, the DCs and research teams have elucidated the roles of key proteins (e.g. histones, GAS6-TAM receptors, and HMGB1) in sepsis pathogenesis. These findings contribute to a deeper understanding of the molecular mechanisms underlying sepsis and support the identification of appropriate protein targets to improve sepsis treatment.
WP2, DCs 5-7 have developed and applied innovative technologies, such as artificial intelligence and machine learning (AI/ML), to support and accelerate the drug discovery process. Novel compound candidates targeting key protein targets (e.g. HMGB1, PAD4, and histone H3) have been identified, and experimental validation to assess their biological activities is currently ongoing. Preliminary results indicate that several compounds show promising activity, for example exhibiting IC₅₀ values in the low micromolar range. In addition, DC8 has successfully established a zebrafish model for sepsis and sepsis-associated encephalopathy (SAE). Taken together, the identification of new inhibitors, the development and application of AI/ML-based drug discovery technologies, and the establishment of a zebrafish sepsis model have significantly advanced the relevant research fields.
WP3, DC9 and DC10 have identified new biomarkers for sepsis diagnosis. Blood samples from 51 critically ill patients at Uppsala University Hospital ICU have been collected and, with consortium support, shipped to Maastricht University for analysis of cell-free DNA and histones. DCs also conducted a secondment at the Institute of Biomedical Research in Barcelona to measure additional biomarkers such as GAS6-TAM and HMGB1. Patient recruitment is ongoing to strengthen correlations between biomarker levels and sepsis severity. Furthermore, DCs and supervisors developed a severe large-animal (pig) model of septic shock.
WP2, DCs 5-7 have developed and applied innovative technologies, such as artificial intelligence and machine learning (AI/ML), to support and accelerate the drug discovery process. Novel compound candidates targeting key protein targets (e.g. HMGB1, PAD4, and histone H3) have been identified, and experimental validation to assess their biological activities is currently ongoing. Preliminary results indicate that several compounds show promising activity, for example exhibiting IC₅₀ values in the low micromolar range. In addition, DC8 has successfully established a zebrafish model for sepsis and sepsis-associated encephalopathy (SAE). Taken together, the identification of new inhibitors, the development and application of AI/ML-based drug discovery technologies, and the establishment of a zebrafish sepsis model have significantly advanced the relevant research fields.
WP3, DC9 and DC10 have identified new biomarkers for sepsis diagnosis. Blood samples from 51 critically ill patients at Uppsala University Hospital ICU have been collected and, with consortium support, shipped to Maastricht University for analysis of cell-free DNA and histones. DCs also conducted a secondment at the Institute of Biomedical Research in Barcelona to measure additional biomarkers such as GAS6-TAM and HMGB1. Patient recruitment is ongoing to strengthen correlations between biomarker levels and sepsis severity. Furthermore, DCs and supervisors developed a severe large-animal (pig) model of septic shock.
In WP1, we have gained insight into the molecular mechanisms of the DAMPs–NETs cycle driving the pathogenesis of sepsis. Several in vitro, cell-based, and in vivo experiments have been established. WP2 focuses more on technology in drug discovery and development, and we have developed novel AI/ML-based tools that can be utilized in the drug discovery process. These innovative approaches demonstrate higher performance in terms of both calculation speed and hit rate. At present, all projects in WP2 have reached a critical milestone, transitioning from in silico outputs to experimental testing of candidate compounds. The identified compounds will be tested in various experimental setups, including in vitro, cell-based, and animal models, supported by beneficiaries in WP1, WP2, and WP3. In WP3, we have investigated and correlated different biomarkers with the condition of sepsis. The results derived from these studies will contribute to more accurate diagnostics. Moreover, a large-animal (pig) model of septic shock has been successfully developed.
Overall, the project is progressing in the right direction to make a significant impact on sepsis diagnosis and treatment. The next critical step is to validate the biological activities of the identified compounds from WP2 across various experimental setups (WP1–3). Subsequently, a cycle of lead optimization (WP2) and experimental testing (WP1–3) will be performed to improve binding affinity, pharmacokinetics, and the chemical and physical properties of the lead compounds. Ultimately, the lead compounds are expected to exhibit therapeutic benefits in mouse and pig models of septic shock. These lead compounds can be further developed into drugs and may also be modified for use as diagnostic tools for sepsis therapy, potentially bringing a substantial impact to society.
The drug discovery process is inherently long, typically taking around 15 years. Currently, the project is still in the early phase and has not yet started the intellectual property rights (IPR) process. However, as soon as we identify the potential to patent and protect the products, such as novel inhibitors or innovative AI/ML-driven drug discovery tools and novel experimental setups/approaches, we will involve relevant participants, including, the developers, the IP manager, the Steering Committee (SC), and others mentioned in the proposal, to initiate the IPR strategy.
Overall, the project is progressing in the right direction to make a significant impact on sepsis diagnosis and treatment. The next critical step is to validate the biological activities of the identified compounds from WP2 across various experimental setups (WP1–3). Subsequently, a cycle of lead optimization (WP2) and experimental testing (WP1–3) will be performed to improve binding affinity, pharmacokinetics, and the chemical and physical properties of the lead compounds. Ultimately, the lead compounds are expected to exhibit therapeutic benefits in mouse and pig models of septic shock. These lead compounds can be further developed into drugs and may also be modified for use as diagnostic tools for sepsis therapy, potentially bringing a substantial impact to society.
The drug discovery process is inherently long, typically taking around 15 years. Currently, the project is still in the early phase and has not yet started the intellectual property rights (IPR) process. However, as soon as we identify the potential to patent and protect the products, such as novel inhibitors or innovative AI/ML-driven drug discovery tools and novel experimental setups/approaches, we will involve relevant participants, including, the developers, the IP manager, the Steering Committee (SC), and others mentioned in the proposal, to initiate the IPR strategy.