Yersinia pestis (Y. pestis), the causative agent of plague, is a Gram-negative bacillus that is classified as a Category A pathogen by the Centers for Disease Control and a logical choice as a biological weapon. It has the potential to generate mass casualties and initiate a global epidemic of pneumonic plague. A major virulence factor for Y. pestis is endotoxin [lipopolysaccharide (LPS)], a glycolipid moiety and a primary component of its outer wall that contributes to Y. pestis induced acute lung injury (ALI) and septicemia in animals. In the lung LPS causes structural changes in the microvasculature resulting in ALI. In animals, LPS-induced ALI is blocked by A1 adenosine receptor (AR) antagonists. Moreover, LPS binds to and activates A1 ARs on human pulmonary artery endothelial cells to induce the release of substances which are cytotoxic to endothelial cells thereby initiating the cascade leading to ALI. Endacea, Inc. is a biopharmaceutical company developing a series of proprietary A1 AR antagonists as anti-endotoxin drugs. With funding from SBIR/STTR grants from NIAID, proof-of-concept (POC) has been demonstrated for its 1) lead molecule A1 AR antagonist, L-97-1, as an anti-endotoxin treatment in an animal model of Gram- negative septicemia (cecal ligation and puncture), and 2) clinical endotoxin diagnostic as a biomarker for Gram-negative septicemia in human clinical trials. These studies validate the A1 AR as an important therapeutic target for Gram-negative septicemia. The purpose of this SBIR Phase I grant is to evaluate L- 97-1 as an anti-endotoxin agent in a bioterrorism model of pneumonic plague. Following inhalational exposure to Y. pestis, rats will be treated with L-97-1, antibiotics, or L-97-1 in combination with antibiotics. Primary outcome measures will be ALI (lung histopathology and wet to dry ratios) and 5-day mortality. To confirm that endotoxin plays a pivotal role in Y. pestis induced ALI, correlation of plasma endotoxin levels with the severity of ALI as a function of the dose for Y. pestis will be determined. To confirm that L-97-1 produces efficacy in this bioterrorism model of pneumonic plague by acting at the A1 AR, radioligand and functional pharmacological assays for ARs will be conducted in rat lung. With successful completion of the studies described in this SBIR Phase Igrant, Endacea will apply for an SBIR Phase II grant to fund: 1) additional animal studies to validate efficacy of L-97-1 as a treatment for pneumonic plague following aerosolized delivery of another more virulent strain of Y pestis, 2) additional toxicology and safety studies for L-97-1 to support an IND, and 3) First Time in Man (FTIM) clinical Phase I studies to demonstrate safety for L-97-1 in humans. Considering the limited window of opportunity to effectively intervene after respiratory exposure to pathogenic strains of Y. pestis, rapid therapeutic modulation of pneumonic plague-associated ALI by novel treatments such as L-97-1 could be essential to national biodefense. ? ? ?
| Wilson, Constance N; Vance, Constance O; Doyle, Timothy M et al. (2012) A novel post-exposure medical countermeasure L-97-1 improves survival and acute lung injury following intratracheal infection with Yersinia pestis. Innate Immun 18:373-89 |
| Doyle, Timothy M; Matuschak, George M; Lechner, Andrew J (2010) Septic shock and nonpulmonary organ dysfunction in pneumonic plague: the role of Yersinia pestis pCD1- vs. pgm- virulence factors. Crit Care Med 38:1574-83 |
