Medical Device Daily Washington Editor

WASHINGTON – The medical device industry has had considerable leeway in the cardiovascular market up to this point in medical history, but despite the hyperbole regarding the prospects for biological fixes for the “old ticker,” stem cells and gene therapy are starting to creep onto the practicing cardiologist’s radar screen.

Little is likely to change over the next couple of years, but should only a modest percentage of the current and future research in these areas pan out, makers of cardiac rhythm devices and artificial valves — as well as the makers of many of the current crop of drugs indicated for these conditions — may find themselves pushed to the margins of this market despite the ample supply of patients who will need help for their aging hearts in the next few decades.

At the Transcatheter Cardiovascular Therapeutics conference Tim Henry, MD, an interventional cardiologist at the Minneapolis Heart Institute (Minnesota) gave an overview of the current state of the research concerning the use of stem cells to treat congestive heart failure and other diseases.

“Right now, there’s too much controversy and, on the other hand, too much hype” surrounding this research, Henry said. He argued that the current spate of controversies is focused on a particular kind of stem cell, which he termed “the wrong question,” adding that there are a number of stem cell types in the adult human body, all having at least some therapeutic potential. The first question researchers should ask, he said, is “what condition am I trying to treat?”

“Can end-stage heart disease be treated with stem cell therapy?” Henry asked, replying that “the quick answer is a controversial probably ‘yes’ — to some extent.”

He noted that the ability of stem cells to release needed biochemicals to nearby cells, commonly referred to as a paracrine mechanism, is probably as vital a part of their ability to repair organs as anything else. However, he predicted that in the future, “stem cells could be used as couriers to deliver gene therapy.”

As for diseased hearts, there are “really not a lot of hard data” for this, he said.

One of the studies referred to by Henry appeared in the September 2004 edition of Circulation, by Emerson Perin, MD, director of new cardiovascular interventional technology and associates at the Texas Heart Institute (Houston). It described the injection of a patient’s own bone marrow mononuclear cells in an effort to treat ischemic cardiomyopathy.

The authors acknowledge, however, that they do not know which of the mononuclear stem cells found in the bone marrow are responsible for some of the observed ameliorative effect on ischemic myocardium. These include mesenchymal stem cells, stem cells that are progenitors of hematopoietic and endothelial cells, and those stem cells responsible for generating various lymphocytes.

They say that the study demonstrated safety by virtue of having triggered no immune response and the results indicate statistically significant improvement in exercise capacity and reduced symptoms of angina. On the other hand, the trial enrolled only 23 patients, nine of whom were controls.

Henry briefly discussed the recently completed Phase I trial for Provacel, made by Osiris Pharmaceuticals (Baltimore), intended to treat myocardial infarction by means of mesenchymal stem cells. In the animal models, the mesenchymals migrated to the heart by homing in on the source of markers of inflammation. But the cells in the Provacel trial will follow inflammation markers to other parts of the body. Lacking any biological trail, the mesenchymal cells head for the bone marrow, essentially going home if there is no work to be done.

Henry said that this early work “absolutely does not” prove efficacy, but he noted that the trial made use of allogeneic cells, which “raises the possibility of one healthy donor” who can donate stem cells to many others, calling this “a huge step forward.”

Nicolas Chronos, chief scientific officer at the American Cardiovascular Research Institute (Atlanta), outlined the current state of gene research into heart disease, noting up front that “a whole gamut of cells are involved” in the inflammation leading to atherosclerosis,” thus offering a range of potential tools, but also requiring a wide range of expensive and time-consuming research.

At present, reduction of low-density lipoprotein (LDL) is really the mainstay of clinical practice for cardiologists, and that as things stand, “we’re treating the end stage” of atherosclerosis, Chronos said. Gene therapy holds out hope of intervening before a heart becomes heavily diseased, but some research seems geared to bypassing genes altogether.

“We can think of gene therapy as just another way of delivering proteins,” said Chronos, hinting that proteomics may move past genomics as the most promising area of research. One of the confounders of any such research, he said, is that patients who have been treated for various heart diseases “have a very, very high incidence of the placebo effect,” producing failure in several trials.

One approach to fending off atherosclerosis, Chronos said, might be to target a gene such as hypoxia-inducible factor (HIF 1), which he said embodies “the cell’s ability to measure the latent oxygen in the environment” and correlates with the onset of atherosclerosis. HIF 1, he said, can induce angiogenesis and could play an important role in treating heart disease.

At present, Genzyme (Cambridge, Massachusetts) has an HIF 1 product in Phase II clinical trials to deal with vascular disease in the lower extremities, and the National Cancer Institute is recruiting for a Phase I trial to see if topotecan hydrochloride can suppress HIF 1 and hence cut off the blood supply in an unspecified group of cancerous tumors. These efforts, however, will not likely result in very near-term clinical application, he said.

As something more promising, Chronos discussed research at the University of Pennsylvania School of Medicine (Philadelphia) involving intravenous delivery of an adenoviral source of human apolipoprotein E (apoE) in apoE-deficient mice to see if this xenogeneic source might prevent atherosclerosis. The research team, headed by Ken Kitajima, MD, found that “extensive atherosclerosis was present in the thoracic aortas and aortic roots” of the controls after one year of treatment but that atherosclerosis “was completely prevented” in the experimental group.