Novel Therapy for Sepsis

A University of Pittsburgh researcher has developed a novel treatment for sepsis and other lipopolysaccharide-associated conditions. The treatment, polypeptide A4-198, can suppress cytokine surges across multiple organs providing protection against endotoxin-induced sepsis. A4-198 prevents overexpression of cytokines, thereby lowering the risk of endothelial dysfunction, microvascular failure and mitochondrial dysfunction, and could potentially provide vital treatment for sepsis by limiting long-term organ damage or death in patients.

A novel engineered polypeptide, A4-198, can suppress cytokine surges in animal models of sepsis. Treatment with A4-198 reduced the risk of death and organ damage in LPS-induced sepsis models, even when delivered 12 hours after sepsis onset. This novel polypeptide has the potential to reduce the cytokine surges responsible for sepsis. 

Description

Sepsis, a life-threatening condition where the body overreacts to an infection, is one of the leading causes of death globally. During sepsis, the body produces excess cytokines including IL-, IL-6, and TNF- which can lead to organ failure and death. There is no currently approved therapy to target these cytokine surges and the development of a treatment targeting cytokine production in patients with sepsis could address this critical therapeutic gap. Lipopolysaccharide (LPS) produced from gram negative bacteria is an upstream trigger for these cytokine surges making this pathway a novel treatment target for sepsis. Animal studies confirm A4-198 can blunt LPS-induced cytokine surges, reducing the risk of organ damage and death in sepsis models and could provide a new tool in the armamentarium against sepsis.

Applications

• Sepsis
• Organ failure
• Pulmonary disease
• Severe infections

Advantages

Current sepsis treatment includes treating the underlying infection, surgical removal of infected areas, and organ support (e.g., ventilator) but fails to target the cytokine surge responsible for sepsis. This novel therapy, A4-198 dampens the body’s over-reaction to infection through down regulation of cytokine signaling and decreasing neutrophil and macrophage levels to acceptable levels. A key advantage of A4-198 is that it has no antibacterial properties and will not contribute to antimicrobial resistance in patients with sepsis. Additionally, A4-198 is highly tolerable in animals with a maximal tolerable dose more than 10 times that of previously identified peptides.

Invention Readiness

A4-198, a polypeptide, was produced. In murine models of LPS-induced sepsis, treatment with A4-198 improved survival rates and protected organs from damage with protection most pronounced in the lung and colon. Treatment with A4-198 resulted in suppression of IL-, IL-6, and TNF- expression in all organs and a decrease of neutrophil levels in the blood, suggesting A4-198 could be developed as a novel treatment for sepsis.

IP Status

Patent Pending