It turns out that developing biological therapies has been fraught with difficulty. Over the years, the use of monoclonal antibodies to treat a number of diseases including cancer took over 30 years to come to full clinical development. Now, anti-HER 2 neu is being used routinely in clinical practice. The development of proteins for cardiovascular disease has encountered difficulties with the application of something as simple as nesiritide (brain natriuretic peptide). These issues point to the difficulty of moving biologic agents to clinical trials and ultimately to efficacy.
I would like to briefly frame my comments in terms of gene transfer and cell delivery, which I refer to as “fraternal twins”. They have many similarities and many differences. In terms of similarities, there has been excessive hyperbole on all counts in the fields of gene and cell therapy. Much of that hyperbole was based on excellent experimental data on normal animals or minimally modified animals, and that both gene and cell therapy have this feature. Early clinical translation has been accomplished by pioneers who are in this room today and others elsewhere which have moved studies from juvenile mice to atherosclerotic elderly human beings very quickly. Indeed, these studies have been so early that a lack of mechanistic studies in humans has often blurred the applications and the results. And indeed, in both of these fields, there is an intense need for bedside-to-bench translation; that is, taking the results of the clinical studies back to the lab to test hypotheses generated within the clinical studies. Who would have thought that it would be better to give cells following acute myocardial infarction at 7 days rather than at 5 days? There is an intense need for this kind of research in these two fields.
But there are differences between gene and cell therapy. The differences include the regulatory milieu. The regulatory milieu for gene therapy was intense and particularly intense outside the United States, where concerns about genetic modification were very strong. The concerns within the United States have been strong and highly regulated, both the by U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH). Because of this, gene therapy proceeded more easily in the United States than in Europe, whereas in cell therapy, it’s just the opposite. In the United States, if a cell is removed and put back into even the same individual for another purpose — that is, bone marrow to grow endothelial cells or a skeletal myoblast to differentiate into a myocyte, it is considered a drug by the FDA and is regulated like a drug. In the United States, this is very complex and takes a great deal of time, whereas in Europe, South America and in China, cell delivery is regulated in a different fashion. Thus outside the United States, we have seen a proliferation of small clinical trials.
What about other features of cell and gene therapies?
Safety profile: Perhaps it’s not as different as we initially thought. The concerns about safety were much greater for gene therapy than they were for autologous cells, although both have proven to be incredibly safe in terms of their early studies.
Geography: Cell therapy is predominantly taking place outside the United States. The majority of studies are from Western Europe, and many South American and Asian studies are underway.
Intellectual property: The role of intellectual property in cell therapies mainly focuses on cell processing. In gene therapy, the vector is the product and can be patented.
Combination therapies: I believe that cell therapy and gene therapy, either directly or indirectly, may be combined in the future to offer some interesting possibilities. I think that genes could be delivered to cells to improve the cellular characteristics, either in terms of survival — which is what Victor Dzau has done with delivering AKT-modified mesenchymal stem cells — or in terms of retaining the cells at the site of delivery.
Many of the effects that Dr. Henry and others have shown here are not necessarily direct cellular effects, but are paracrine effects mediated by growth factors and cytokines, which cells produce. Cells are bags of genes and gene products, and so they could be modified using vectors to improve their effects. Gene delivery alone is fraught with difficulties in terms of delivery retention, but a cell, even with limited cell delivery, is in general better than the best gene delivery. Thus even if the cell was there to provide an inert method of delivery, gene delivery via a cellular approach might be very important.
A final part of an effective combination would be devices. I think a biologically modified device may be something that could be practically and inherently simple to use. We have been working on one such device and have devised a system of using paramagnetically labeled cells and adding magnetic properties to standard stents to deliver. We have done this with stents, with grafts, and we are doing this with LVADs. Thus, a strategy to change the biological properties of a device using a biological mediator such as a cell or a protein or a viral vector might be another combination therapy that we will see in the future. Thank you.