Treatment of Sepsis and Acute Respiratory Distress Syndrome (ARDS)

Challenge

Severe sepsis is a leading cause of death among critically ill patients in non-coronary intensive care units (ICU). Respiratory tract infections, particularly pneumonia, are the most common site of infection, and associated with the highest mortality. The type of organism causing severe sepsis is an important determinant of outcome, and gram-positive organisms as a cause of sepsis have increased in frequency over time and are now more common than gram-negative infections. In the United States, the incidence of severe sepsis is estimated to be 300 cases per 100,000 population (>0.5 million cases per year, with at least a third being lethal).

The acute respiratory distress syndrome (ARDS), which is characterized by a combination of lung edema and acute inflammation, continues to be a major health care problem, affecting more than 190,000 people in the US annually with a mortality of 27-45% depending on the severity of the illness and co-morbidities. Estimates from prospective US cohort studies range from 64.2 to 78.9 cases per 100,000 persons per year.

Sepsis and ARDS are frequent and extremely severe conditions very often leading to the death of patients. The high mortality in sepsis and ARDS points to the low efficiency of existing treatment modalities and justifies the need for development of novel methods and drugs for therapy.

Technology

The invention suggests a novel chemical scaffold based on a modified structure of oxidized phospholipids (OxPLs). As compared to natural phospholipids, novel OxPLs are modified in a way to increase bio-stability and simplify synthesis of individual molecular species. These OxPLs demonstrate two biological activities. First, the molecules are dual inhibitors of Toll-like receptors 4 and 2 and thus they can inhibit pro-inflammatory action of both Gram-positive and Gram-negative bacteria. Second, the molecules enhance endothelial barrier in lung vessels thus preventing development of lung edema. Because systemic inflammation and impairment of lung barrier is often observed in the same patients, poly-pharmacological action of these OxPLs may be especially effective for treatment of such severe combination cases.

The novel OxPLs demonstrate similar or better anti-LPS and endothelial barrier-protective activities as compared to natural phospholipids. In addition, the OxPL-scaffolds can be a carrier for other barrier-protective drugs such as iloprost thus enhancing their action and increasing duration of protective effect.

Commercial Opportunity

Collaboration, License, Purchase

Development Status

In vitro POP: novel OxPL-prostanoids inhibit inflammatory effects of LPS in vitro and protect endothelial cell barrier, novel OxPL-conjugated iloprost demonstrated stronger and more prolonged barrier-protective activity as compared to iloprost.
In vivo POP: novel OxPL-PGE2 inhibit induction of inflammatory chemokine KC in mice injected with LPS, novel OxPL-iloprost demonstrated better protection from edema in vivo as compared to iloprost.

Patent Situation

US Priority application 8/2017

Further Reading

Oskolkova OV et al. Incorporation of iloprost in phospholipase-resistant phospholipid scaffold enhances its barrier protective effects on pulmonary endothelium. Sci Rep. 2018 Jan 17; 8(1):879
Mauerhofer C et al. Hormetic and anti-inflammatory properties of oxidized phospholipids. Mol Aspects Med. 2016 Jun; 49:78-90
Oskolkova OV et al. Oxidized phospholipids are more potent antagonists of lipopolysaccharide than inducers of inflammation. J Immunol. 2010 Dec 15; 185(12):7706-12
Bochkov VN et al. Generation and biological activities of oxidized phospholipids. Antioxid Redox Signal. 2010 Apr 15; 12(8):1009-59