Initial developments of regenerative therapies were mainly angiogenesis gene therapy approaches for therapy-refractory angina. We are here to remember Andreas Gruentzig as the pioneer in interventional cardiology, but I would also like to remember the pioneer in angiogenesis gene therapy, Jeffrey M. Isner, who I have had the privilege to work with. I did not have the opportunity to get to know Andreas Gruentzig personally, but I did have the privilege to work with the late Jeffrey Isner, who died in the meantime, following an acute MI at the age of 53.
The pictures demonstrated here are from the first publication of the intramyocardial application of gene therapy published by Jeff’s coworker, Douglas Losordo, who also became his successor, leading the research group formed by Jeffrey Isner. Those clinical data stem from 1998, but it was as early as 1991 when we did the first experimental work in pig hearts, performing intramyocardial injections of gene constructs in Jeff’s lab. One of the major questions to be answered was, Which would be the best vectors for gene transfer? The winners in cardiovascular gene therapy became plasmids and adenoviral vectors. The other big question, of course, was , What would the best route be to apply those genes to the myocardium? First, direct myocardial injections during bypass surgery were used as approach. Today, applications tend to be more catheter-based following the development of numerous catheter systems that allow for the guiding of catheters within the left ventricle. The first work published in this regard came again from the Isner group using the NOGA system for catheter-based intra-myocardial injection of genes. In more recent studies, the same system has also been used for the application of stem cells.
Development of stem cell therapy for myocardial infarction has been much more recent — but it was basically gene therapy that paved the way, with the same applications routes already available tested in similar animal models with, in part, identical endpoints. Improvement of pump function was the endpoint in most cardiac stem cell studies to date, but at this meeting, we will also, for the first time, hear about unpublished data from the first placebo-controlled trial on stem cell therapy for therapy-refractory angina.
Recently, our group looked at the improvement of arrhythmias in experimental mouse and rabbit models. Results are promising, as mobilization of bone marrow cells using granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) led to a reduction of inducible ventricular tachycardias (Kuhlmann et al. J Exp Med, 2006). Thus, treatment of malign arrhythmias following myocardial infraction may be another good endpoint for stem cell therapy. With the many different cell types that can be used for stem cell therapy, it is not yet clear which are the most promising. Also, the question remains whether cells need to be extracted from the body and later re-injected, or whether mobilization of stem cells, including resident stem cells in the different target organs, will be sufficient. There is increasing evidence that most stem cells actually do not integrate into the target organs, nor do they differentiate in functioning cells. Thus, beneficial effects may rather be via paracrine actions of factors released that are probably mostly angiogenic. Indeed, as a substrate for possible improvement of ventricular function or arrhythmias, angiogenesis or arteriogenesis was primarily observed in the tissue following stem cell therapy. To make the system even more complicated, there is evidence for direct therapeutic effects and autocrine loops of cytokines like G-CSF used to mobilize hematopoietic stem cells from the bone marrow.
Today, Bill O’Neill will focus on stem cell therapy for acute myocardial infarction. Following Bill’s talk, Joseph Babb will discuss the various devices for intramyocardial application catheters. In the following presentation, Jorge Belardi will present the Argentinean experience with gene and stem cell therapy. Tim Henry will then report the first placebo-controlled stem cell trial on therapy-refractory angina, which is unpublished data. Robert Simari will discuss the concepts of stem and gene therapy combinations. And finally, to finish this session, I will present the mechanisms of cytokine therapy for the mobilization of bone marrow, which are data in press.