Theme 4 - Clinical translation

Evaluating clinically-relevant GMP-compatible human cell types in an advanced porcine model of closed chest balloon MI with immunosuppression

Under Theme 4 we will test in an advanced porcine model of MI the three human cell types developed by our scientists including BOECs cells, CD16+CD56- pro-angiogenic monocytes and pericytes. Translation of these cell-based treatments to bed side require the testing of their safety and efficacy in advanced experimental models operated by clinical experts at NHS and GLP standards and highly relevant to human. To be meaningful, these evaluations need to be based on the same quality of in-vivo imaging used in the NHS. In Theme 4 of our Centre, we are using this rigorous preclinical testbed approach taking advantage of the BHF and MRC co-funded Translational Biomedical Research Centre (TBRC) at the University of Bristol.

While prompt diagnosis and early revascularisation plays a key role in limiting the extent of MI, achieving relief of symptoms and reducing the risk of recurrent MI, for those patients suffering significant MI effective therapeutic approaches are required to promote repair or prevent heart failure.

Our goal is to develop adjuvant therapies that promote neo-angiogenesis and modulate repair toward function myocardium instead of scar. To this end, we are investigating multiple approaches ranging from mobilisation of endogenous progenitor cells to delivery and engraftment of autologous or allogeneic cells.

Whilst endothelial, mesenchymal and perivascular cells enhance angiogenesis and reduce infarct size in experimental studies, little effect has been observed on ventricular remodelling, fibrosis and heart failure. We have developed and tested extensively in small rodent, three human cell types with marked pro-angiogenic potential. We are now testing our hypothesis that if these cells are effectively delivered to the myocardial areas at risk earlier after MI they will modulate left ventricular remodelling and improve cardiac function. This key preclinical work is being carried out at the TBRC advanced pre-clinical facility under the clinical leadership of Ascione and Mills. We are using a clinically relevant porcine model of balloon MI with reperfusion to mimic the primary PCI-stenting scenario. MI procedures, modes of cells delivery and in-vivo evaluations are fully established with >98% reproducibility and experimental completion rate.

Principal investigators

Raimondo Ascione, Nick Mills (Leads), Paolo Madeddu, Ajay Shah, Andrew Baker