Tissue Engineering and Interventional Cardiology

George Dangas: There have been many attempts and many failures in this field due perhaps to the inherent tendency of interventional cardiologists to move quickly and work from assumptions, applying what may not yet be well understood. Gene therapy and engineered viruses (associated viruses, attenuated viruses, etc.) are examples of this. When it became clear that we were unable to identify the most appropriate and effective agent for angiogenesis, we looked toward the newly fashionable stem cell-based therapies. Even researchers make 3 million agents, and 2 of them turn out to be effective, that would be fine. On the other hand, perhaps the stem cells will produce 2 or 3 agents that work for angiogenesis, but at the same time, 1 or 2 other agents produce negative effects — the result being that the positive effect hoped for is not achieved. Thus, the interventional cardiology field must achieve more “crisp” results based on more “crisp” basic science, with better-established findings, in order to better understand what the targets are and pursue them in a more methodological manner. Our methodology needs to be evidence-based, as opposed to the focusing on the practicalities of how to achieve our aims. We need to scale down the in vivo applications and return to the laboratory. David Holmes: There are a number of small, randomized trials currently under way, primarily in Europe. Perhaps some of our European colleagues here could discuss these trials. We are already in the middle of human trials before obtaining adequate scientific data about which specific cells to use, how many cells, when to deliver them, and how to deliver them. Is that a good thing? What if they fail? does that mean the approach is wrong? Or does it mean that we were doing it incorrectly? Peter Gonschior: The good thing is that very robust cells are used based on solid, basic scientific data. That led to the application of a large variety of cells, which led to what appeared to be good data. The patient data, such as ejection fraction, however, are not terribly impressive. Ejection fraction improvement is not very significant, especially when you factor in the amount of energy wasted to achieve any clinical impact in the patients. More basic, relevant data are required to guide us toward the best approach. Wolfgang Ritter: We have never used drug-eluting stents, so we wait to see what the cardiologist does. David Holmes: From the industry standpoint, it would be nice to have a patentable product so that the product’s unique design bearing the corporate name could be marketed. Given that God invented the progenitor cells and has a pretty strong patent on them, how do we “patent” a cell? For example, a bone marrow cell injected in the coronary artery — how do you design a device to do that? How do you make a living at that, since most any device could do that task? Brian Firth: Let me come at this from a different angle. For some time now, Cordis has looked at what it already had as facilitating technology. We have been on the delivery side of the business, specifically with our Noga systems, the NogaStar®, the MyoStar™ injectable catheter, and so on. Thus, the mapping, definition and ability to deliver something in a very site-specific manner constitute the piece of the business Cordis has focused on. Having said that, in order to obtain 510-K FDA device approval, we must prove that it actually does something. Thus, Cordis is currently working on the area of autologous bone marrow with stem cells. Our interest is not in trying to figure out how to patent stem cells, which can’t be done, but rather in the delivery of these cells, because we think that a more local delivery system would be better than a more general one. Cordis seeks to design a system, thus, that would deliver the cells that have been identified for their contractile properties to a site that has been defined as compromised. Richard Heuser: These are expensive studies to conduct, thus, if the product is not patentable, it will not attract industry funding. In the case of the Bioheart study, how will this trial be conducted? Will sham cells be given, or no cells, or a small number of them? Also, we want to target the patient population that is not eligible for heart transplants. We have been talking about bone marrow cells as well. My understanding is that there is a very good possibility that these cells can be delivered intravenously with the same results. So how do we design, say, a skeletal muscle cell study that would actually end up garnering FDA approval for the therapy? And what about bone marrow — is it really necessary to go down the coronary arteries and go selectively into the myocardium? David Holmes: Those are two important questions. Bioheart is a skeletal muscle myoblast product. The company considered this product a drug when it applied to the FDA for approval. In drug trials, the FDA requires data on ineffective dosage in addition to a toxic dose, and a couple of doses that do work. Thus, the first dose in the Bioheart project that was approved by the FDA was absolutely ineffective — it might as well have been placed under the patient’s pillow. The data that came out of Europe on Bioheart involved a much higher dose, albeit with a small number of patients. In terms of the second point as it relates to where and how to administer the cells, some information has shown that when these different sorts of cells are delivered intravenously, they go to the lungs and have a “tremendous time,” and they don’t reach the myocardium. So while it makes perfect sense to use the intravenous approach, these cells are filtered out in the lungs and remain there. If those cells are active and produce cytokines, perhaps that’s all we would want to use them for. Maybe these cells aren’t the magic solution, and maybe we don’t have a clue about this. Perhaps we can use these cells for the cytokines they produce systemically and they will cause other bone marrow cells to hone in on the site of injury. But at the present, we just don’t know enough about this process. Patrick Whitlow: I just want to give you an update on Bioheart because of their underlying disease process, these patients are very prone to arrhythmia and sudden death. And theoretically, if you are adding islands of tissue in the left ventricle that is already damaged, these islands of tissue are not enervated in the same way as the surrounding tissue and the conduction properties aren’t the same. You would theorize that this could set up re-entry circuits. Thus, ventricular arrhythmia presents an enormous problem in terms of conducting studies because many of these patients are going to die from their underlying disease. To detect if cell injection causes worsened arrythmias will be very difficult, but a potentially serious problem. Therefore, the first v.s. clinical trial involves patients who already have defibrillators, and the number of patients will be small because of the need for defibrillators. The study should answer the question of whether this is arrythmogenic — which Patrick Serruys believes is the case. Other researchers in France don’t believe that injecting cells is arrhythmogenic. Who knows? It will take a long time and a lot of patients to arrive at the answer. If a start-up company tries to make this therapy work, it will be very difficult for industry to actually fund the research from start to finish. We know from the animal studies that efficacy increases with higher doses of cell therapy, but we have yet to find what a potentially toxic dose is for the size of the island of cells that produce arrhythmias. I think that the bulk of this research will have to be federally funded. It’s all very interesting work, and according to the animal models, it should work in humans. David Holmes: Although the skeletal myoblasts appear to be arrythmogenic, it appears to relate to engraftment properties. With true stem cells — whatever they are — it doesn’t seem to be as problematic, whether because there have so far been very small numbers of patients, or whether indeed these stem cells are more pluripotential and engraft better, or whether they are more homogeneously distributed, and aren’t just islands. It is early in this field, and I would echo what George said: in a field where so much rides on a product or technique, some of the trials are too premature because we often don’t have the necessary solid scientific underpinnings before launching an important large trial. The biggest potential problem downstream to this approach is that if the product fails, we don’t know for certain whether failure was due to the product’s ineffectiveness or because we didn’t know how to properly use it. George Dangas: I would like to comment on interpreting the data from some of these early studies. I don’t think we have the proper tools to accurately study the early results. The preliminary decision by the Rotterdam group was to implant defibrillators in all patients of the Bioheart study after two or three deaths occurred in one arm. Still, we haven’t figured out whether it was actually the number of implants or if it was a patient substrate with a number of implants that caused the arrhythmogenecity. I think that any other study at this stage would produce statistical errors in both directions, which makes it very difficult to determine whether it was a failure of the agent, the liver system, or that the patients in the treatment arm were too sick and were going to die anyhow. That last explanation is a possibility because, due to ethical considerations, we usually enroll “no option” patients for these types of agents. Richard Heuser: The Bioheart study involves a specific, patentable therapy which provides greater incentive to the company to see the project through to the end. One thing that always concerns me is determining what the endpoint will be. We all love to see those ejection fractions, but I think that the two main endpoints will likely be treadmill time (endurance) and objective findings of symptom relief. A third endpoint might be the number of hospitalizations for congestive heart failure. I agree that we have to conduct this study in some sort of randomized fashion. I think that the low-dose cells which we discussed will be a good way to do it. Also, since it’s a very small number of patients being subjected to this very expensive therapy, I wonder if we could collect data on the patients before we commence therapy. In other words, we would assign the patient. We all know how long it takes to enroll patients in this trial; there’s a lot of information to gather. During the six-month lead-in period, more data points could be obtained by looking at retrospective data on those individual patients. It won’t be enough to see the ejection fraction increase, and there certainly won’t be a reduction in mortality. David Holmes: I think there will be a reduction in mortality rates and it will be the lead-in phase. For instance, all of the transplant centers have patient deaths while on the waiting list. This study will provide the same type of information. There may be other endpoints — viability of MR, for example. Whether viability with MR will be an “approvable” endpoint remains to be seen, however. We will need to be creative in terms of endpoints. William O’Neill: I agree with you, George, in terms of the degree of our ignorance about the basic science in this area. My own feeling is that God — or nature — in His infinite wisdom, is a lot smarter that we will be for a few centuries yet in terms of the cascade of processes that actually allow a new cell to come in and regenerate. It is a little foolhardy to say that we should wait until we completely understand these processes before any clinical trials are launched. These early attempts are fine, as long as patients aren’t harmed and as long as the patients are properly selected in terms of their ability to spontaneously improve function. As you said, pre-transplant patients will not improve function and there will likely be a big upside and very little downside for them. I would thus encourage conducting these small, mechanistic trials as a means of enlightening us as to where we stand and where we must go. Finally, when we change from the basic experiments to human trials, we are dealing with patients who are on all types of medications. Do ACE inhibitors, calcium channel blockers, beta-blockers and nitrates alter, improve or decrease the ability of cells to regenerate? We simply don’t know the answer to this question. I do believe that we face a long process of trial and error, and will make small advances along the way. David Holmes: I think that view is correct, provided that if the small trials are negative, we don’t then abandon the field and decide that the therapy doesn’t work. It seemed to be the case with some of the gene therapy trials where incredible hype was followed by randomized trials that produced negative results, setting the field back significantly. I think that well-designed studies aimed at identifying mechanisms will be terribly important for the field. Brian Firth: In terms of endpoints, I believe that this falls under the same rules as most of the heart failure studies. The FDA wants to see that therapies designed for patients with heart failure or impending heart failure don’t increase mortality while improving other parameters. Thus, researchers don’t have to prove that the therapy improves survival rates, but they do have to prove that it doesn’t adversely affect survival. That was the big lesson learned from the inotropic therapy studies. Thomas McNamara: What has been the progress and/or expectations with other critical organs — namely, the liver and the kidneys? Has work been done in this area? David Holmes: I think work has been done, particularly on the liver, partly because it can regenerate. We tend to think that heart cells will repair what has been a problem, and I don’t know if they will wildly proliferate and make a totally new heart, liver cells can do. You need to understand that I’m not exactly sure where in the abdomen the liver resides, so I’m perhaps not the best person to ask!