Project Portugal 2030

Summary

Despite three decades of research and numerous clinical trials, a specific and efficient treatment for human sepsis remains elusive. Presently, the management of human sepsis basically relies on infection control and extended life support, with no immunomodulatory strategy proving efficient thus far (5). Many promising treatments showing efficacy in mouse models have failed in clinical trials. Failure may be attributed to various factors, including inadequate protocol designs that do not replicate the clinical situation. For instance, many studies report the administration of drugs prophylactically or coincidentally with the infectious insult, which does not mirror standard clinical care practices. Additionally, common sepsis comorbidities and underlying medical conditions are often disregarded in preclinical trial designs, despite their significant impact on clinical parameters. Recommendations to enhance preclinical trial designs have been proposed, aiming to create more accurate representations of human sepsis (2-4). These include using microorganisms replicating those found in human sepsis, initiating therapeutic interventions after sepsis onset, and exploring sepsis syndromes originating from sites other than the peritoneal cavity, like the lung and urinary tract, as these are of significant clinical relevance. Double-hit models are becoming regarded as more representative of the real context of the condition in humans, where a first non-lethal insult establishes a primary infection, which is then followed by a secondary infection by other opportunistic pathogens. Furthermore, there is a need to develop sepsis models with modifying risks of morbidity and lethality, such as age, diabetes, or cancer. Our previous work studying the effect of therapeutically administered rCD5L in combating sepsis using common preclinical models yielded unmatched efficacies in mouse survival. With a strong candidate in hand, we aim to further explore the benefits of rCD5L therapy using appropriate preclinical models and an optimized drug formulation. The main objectives of the proposal are: 1. Determine the therapeutic efficacy of rCD5L in secondary pneumonia using double-hit models. 2. Determine the therapeutic efficacy of rCD5L in sepsis models incorporating biological factors and comorbidities like age and obesity, leading to conditions such as diabetes and hypertension. 3. Develop and produce engineered bioactive rCD5L, impervious to IgM coupling, and with improved pharmacokinetic properties, stability, and therapeutic efficacy. Using these improved models and tools, we will characterize the mechanisms underlying the protective effect of rCD5L, analyzing biological parameters in treated and untreated infected mice, such as bacterial burden, inflammatory mediators, organ pathology, and immune cell involvement and activation in response to infection and treatment. Our planned research addresses critical challenges, aiming to surpass the boundaries of current knowledge in sepsis research. By exploring new avenues and pushing the limits of traditional methods, we aim to make significant strides in sepsis treatment and translation to clinical medicine.