Project 451591

Sepsis (ie. serious infections of the blood) can cause a vicious cycle of blood clot formation and inflammation, which may lead to multiple organ failure and death. In Canada, there are approximately 90,000 patients with sepsis each year, with estimated mortality rates of up to 30%. Despite decades of sepsis research, there are no anti-sepsis drugs and the mortality rate of sepsis remains high. This suggests that some fundamental knowledge is lacking in our current understanding of why sepsis kills patients. In recent years, neutrophils (a type of white blood cells) have been shown to release web-like structures (called NETs) to capture and kill microorganisms. NETs consist of DNA, histones, and neutrophils enzymes. However, NETs can also cause collateral damage to the body. We have previously shown that the DNA and histone components of NETs can trigger blood clotting and prevent blood breakdown. In a mouse model of sepsis, injection of DNase I (a naturally-occurring enzyme that breaks down DNA) results in improved organ function and improved survival rates. We believe that by giving patients an enzyme that chews the DNA component of NETs, we can break up this clot formation. This drug, called DNase I, is already safely used to digest the NETs formed in lungs in cystic fibrosis patients with lung infections. We are planning a phase 1 study at the Hamilton General Hospital and the Maisonneuve-Rosemont Hospital (Quebec) to assess the safety of giving this drug intravenously to septic patients. We will assess if two different doses (given for either 3 or 7 days) are safe in septic patients. We will also draw extra blood samples before and after the drug is infused to determine the impact of the treatment on NET formation over time. The outcome from this study will allow our team to establish if DNase I therapy is safe in septic patients, which would pave the way for larger studies in the near future to determine drug effectiveness.