The overall aim of this project is to provide a comprehensive assessment of a medically licensed cell therapy product, Cyndacel, in pre-clinical models of systemic sepsis to allow progression to Phase I/II clinical trial for this condition which is currently a critically unmet clinical need. Bone marrow and umbilical cord derived mesenchymal stem cells have demonstrated potential in a variety of pre-clinical disease models, including bacteria derived pneumonia and endotoxin derived systemic sepsis. The Centre for Cell Manufacturing Ireland (CCMI) has recently been licensed to produce medical grade MSCs, and will shortly begin generation of the Cyndacel product, a proprietary, FACS isolated, cellular medicinepatented by Orbsen Therapeutics Ltd. Both of these entities are located at NUI Galway. We will take freshly harvested or cryofrozen Cyndacel MSCs and assess their anti-bacterial potential in vitro against E.coli, a common causative agent in systemic sepsis. Cell culture of lung, liver and kidney cells will assess anti-inflammatory and pro-survival effects of Cyndacel and the Cyndacel secretome against endotoxin. In a rodent caecal ligation and puncture (CLP) model we will administer Cyndacel at a range of timepoints post-injury. A complete profiling of leukocyte subpopulations will be performed to assess modulation of the immune system. Animal physiological parameters such as blood oxygenation, pH and lactate levels will be continually assessed during procedures. Lung function will be measured by static compliance and leukocyte infiltrate count. After sacrifice, blood and major organs (heart, lung, kidney, liver) will be assessed for inflammatory markers by QPCR and ELISA. If a clear benefit it evidenced, we will use the data generated as part of further funding applications to back clinical trials and as part of an Investigator Brochure.
