NETosis
Our immune system is made up of a complex network of cells and molecules that work together to counteract detrimental effects from external pathogens such as viruses, bacteria, parasites, fungi and protozoa, or from the growth of cancer cells. Typically, when a pathogen enters our bodies, it’s entrapped by specific white blood cells, called neutrophils, and is eliminated.
A variety of pathogenic stimuli, such as external pathogens, antibodies and immune complexes, cytokines, microcrystals, or other physiological stimuli can trigger a process called NETosis, the formation of neutrophil extracellular traps (NET). When neutrophils, which represent the most abundant type of white blood cells, are recruited to the site of inflammation, they entrap and eliminate pathogens by expelling NETs into the extracellular environment and eventually undergo spontaneous death.
Under normal circumstances, NETosis is a self-defense strategy. Nonetheless, the formation of NETs can become per se a pathogenic stimulus in many diseases such as cancer, autoimmune diseases (e.g. rheumatoid arthritis), lung diseases, atherosclerosis, venous thromboembolic diseases, and COVID-19.
The role of chemokines in drug discovery
With the intent to address our studies to innovative fields in order to provide novel breakthrough in translational preclinical research, we are striving to develop specific techniques to measure NETosis by analyzing samples of blood, plasma or other biological fluids. Chemokines are critical in the process of NETosis as they are responsible for recruiting neutrophils to the site of inflammation. With the intent to explorate and break through new fields, our research is pointing to elucidate the mechanisms underlying the involvement of chemokines in the inflammatory process and the implications that they may have for drug discovery.
In this view, we have also established several valuable partnerships within the scientific community to accelerate the development of new compounds able to inhibit deleterious NETosis through the modulation of specific chemokines-dependent neutrophil activation.
Chemokines: Key players in innate and adaptive immunity
Our immune system, our defense from disease-causing agents, such as bacteria, viruses, parasites, fungi and cancer cells, is remarkably conditioned by chemokines.
Chemokines are signaling proteins secreted by cells for the recruitment of leukocytes such as of other cell types to sites of inflammation and damage, including neutrophils, that undergo NETosis to eliminate incoming pathogens.
As such, chemokines and chemokine receptors are pivotal to the immune response, therefore becoming a focus for autoimmune diseases and cancer. At Dompé, we are screening novel drugs targeting culprit chemokines to inhibit pathogenic NETosis.
Type 1 Diabetes
Type 1 diabetes is an autoimmune disease in which the body’s immune system recognizes it as a pathogen, attacking and destroying the insulin-producing cells in the pancreas. Insulin is vital for the absorption of glucose into the cells throughout the body. This process is essential as glucose metabolism is the primary source of body energy.
Many people are affected by type 1 diabetes. Just in the US, an estimated 1.84 million Americans have the disease, with a rate of diagnosis increasing every year. Besides the heavy economic/social burden for their family and/or caregivers, a patient’s lifestyle is strongly compromised due to their simultaneous experience of physical impairments and psychological consequences, such as stress and depression.
There’s clearly a high medical need to find a therapeutic strategy to prevent or cure type 1 diabetes. One of our main research objectives is to understand the molecular mechanisms underpinning the NETosis process and to identify novel target drugs. In this context, the ability of Ladarixin, an inhibitor of IL-8 activity, to modulate the autoimmune-mediated inflammatory cascade leading to the progression of type 1 diabetes is currently being studied.
Acute respiratory distress syndrome (ARDS)
ARDS is an acute, inflammatory lung injury characterized by increased pulmonary vascular permeability and significant impairments in lung mechanics and gas exchange.
ARDS is a complex, heterogeneous syndrome with a mortality rate that may exceed 40% and the onset of ARDS can be associated with direct or indirect lung injuries, such as Pneumonia, Aspiration, Sepsis or Trauma. In ARDS, acute inflammation generates severe consequences and eventually leads to a chronic dysfunction of multiple mechanisms through massive cytokine secretion by infiltrating neutrophils, resident macrophages, endothelial cells and infiltrating fibroblasts.
IL-8 levels in ARDS patients have been shown to correlate with a poor progression and outcome of the pathology. To date, Reparixin, an inhibitor of IL-8 signaling, is currently at an investigational stage in clinical application, having previously been shown to be safe and effective at multiple levels in preclinical studies. Indeed, in multiple animal models of acute lung injury (induced by infections or pharmacological treatment), Reparixin was able to: inhibit neutrophil infiltration with reduction of NETosis, restore a partial endothelial permeability and to reduce fibrosis, thus ameliorating general lung respiratory function.
Other areas of research
Dompé is keeping investigating Reparixin in in patients suffering from lung injury caused by complications of COVID-19.
Chemokines Pipeline
| Platform - Asset | Indication | Phase 1 Phase 2 Phase 3 Post-Market |
|---|---|---|
| NETosis - Reparixin | Community Acquired Pneumonia (CAP) | |
| NETosis - Reparixin | Acute Respiratory Distress Syndrome (ARDS) | |
| NETosis - Ladarixin | Type 1 Diabetes – Early Onset | |
| NETosis - Ladarixin | Type 1 Diabetes – Insulin resistant |
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Ladarixin
INN (International Non-proprietary Name): Ladarixin
Ladarixin is an inhibitor of IL-8 activity. It is being studied for its potential of modulating the autoimmune-mediated inflammatory cascade that leads to the onset and progression of type 1 diabetes.
Reparixin L-lysine salt
INN (International Non-proprietary Name): Reparixin L-lysine salt
Reparixin is a non-competitive allosteric inhibitor of CXCL8 receptors, CXCR1 and CXCR2, able to inhibit the intracellular signal transduction events activated by the binding of CXCL8 to CXCR1 and CXCR2. The binding site hypothesis derived through computational studies was confirmed by alanine scanning mutagenesis, and a region in the transmembrane of CXCR1 and CXCR2 was identified.