Pratteln,
Researchers at CSHL are part of a recently formed consortium of international non-clinical and clinical experts called the ‘NETwork to target neutrophils in COVID-19’. This NETwork will study the role of neutrophils and neutrophil extracellular traps (NETs) in the pathology of COVID-19 as well as hNE and other targets for intervention for the purpose of treating COVID-19 [1, 2].
NETs are macromolecular structures of DNA and proteins that neutrophils can expel, for example during severe inflammation. hNE is released by neutrophils when they form NETs. There are clear similarities between the clinical presentation of severe COVID-19 and diseases known to involve NETs, such as ARDS. On this basis, the NETwork has developed the rationale that excess NETs may play a major role in COVID-19 and that inhibition of hNE may be a therapeutic strategy to antagonize NETs in COVID-19 patients.
Santhera will provide lonodelestat and intellectual support for the scientists at CSHL who will conduct the non-clinical research program. The work is expected to further validate hNE as a target and shed light on this clinical stage compound as a potential agent also in COVID-19.
“There is a strong scientific rationale that inhibition of hNE may interrupt a neutrophil-driven inflammatory cascade that leads to ARDS in COVID-19 patients” explained Mikala Egeblad, PhD, Associate Professor at
“We would like to thank CSHL and collaborating clinicians that have approached us to support their efforts to further explore and understand the role of hNE in relation to ARDS in COVID-19,” said
About lonodolestat (POL6014)
Lonodelestat (previously known as POL6014) is a highly potent and selective peptide inhibitor of human neutrophil elastase (hNE). In preclinical studies lonodelestat was effective in animal models of neutrophil activation in lung tissue and of acute lung injury (ALI) [3, 4]. Lonodelestat is an investigational drug which completed Phase 1 single dose escalation studies in healthy volunteers and patients with cystic fibrosis (CF) and is currently investigated in a multiple ascending dose study in CF patients. Current data demonstrated that single dose inhalation of lonodelestat can lead to high drug concentrations within the lung, resulting in inhibition of hNE in sputum of patients, an enzyme associated with lung tissue inflammation [5].
References:
[1] Global NETwork studies role of immune cells in COVID-19 deaths, CSHL Stories and Media
[2] Barnes B J et al (2020). Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J Exp Med (2020) 217 (6): e20200652. DOI: https://doi.org/10.1084/jem.20200652
[3] Sellier Kessler O et al (2018). Effect of POL6014, a Potent and Selective Inhaled Neutrophil Elastase Inhibitor, in a
[4] Lagente V et al (2009) A Novel Protein Epitope Mimetic (PEM) Neutrophil Elastase (NE) Inhibitor, POL6014, Inhibits Human NE-Induced Acute Lung Injury in Mice. Am. J. Respir. Crit. Care Med. 2009; 179: A5668
[5] Barth P. et al (2019). Single dose escalation studies with inhaled POL6014, a potent novel selective reversible inhibitor of human neutrophil elastase, in healthy volunteers and subjects with cystic fibrosis. Journal of cystic fibrosis 2019. DOI: https://doi.org/10.1016/j.jcf.2019.08.020
About human neutrophil elastase (hNE), acute respiratory distress syndrome (ARDS) and COVID-19
Activated or necrotic neutrophils liberate human neutrophil elastase (hNE) in the lung which causes damage to the pulmonary microenvironment. hNE is also a critical enzyme in neutrophils and it is required for neutrophils to form NETs (neutrophil extracellular traps) as part of the body’s immune response. Under conditions of severe inflammation, neutrophils can expel NETs which can aggravate pulmonary inflammation and may contribute to the development of acute respiratory distress syndrome (ARDS). Inhibition of hNE activity may therefore display a dual action: it may block the toxicity of hNE in the lung tissue, prevent the formation of NETs and therefore may allow combating ARDS in patients with COVID-19.
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About the ‘NETwork to target neutrophils in COVID-19’
In the urgent battle to treat COVID-19 patients, a group of eleven international medical research organizations is investigating whether overactive immune cells – specifically neutrophils – via production of neutrophil extracellular traps (NETs) cause the most severe cases. The group, called the NETwork, includes
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