The research program of Dr. Rabinovitch and colleagues focuses on the pivotal role of an elastin degrading enzyme (which they call an endogenous vascular elastase) in the pathobiology of vascular disease.

Release of this enzyme has multiple effects. The breakdown products of elastin, elastin peptides, elicit the accumulation of inflammatory cells. These cells then penetrate the vessel lumen, releasing their own elastases and matrix metalloproteinases. This results in amplification of the proteolytic response. Growth factors normally stored in an inactive form are also released as part of this chain of events.

Inhibiting the activity of endogenous vascular elastase may prevent the events of vascular injury. This research group initially used elastase inhibitors to treat experimental rodent models of pulmonary hypertension.

The investigators first explored the hypothesis that a very aggressive form of coronary artery disease that occurs after heart transplant may be susceptible to treatment with elastase inhibitors. In a rabbit heart transplant model, they found extensive neointimal lesions that partially or almost completely occluded the vessel lumen. In contrast, in animals treated with elafin, a naturally occurring human elastase inhibitor, 80% of arteries maintained a pristine form.

After demonstrating this, the researchers studied elafin in settings where inflammation can contribute to vascular disease. In rabbits, they interposed the jugular vein in the carotid arterial position and infused that vein with a recombinant form of the elastase inhibitor elafin delivered by gene therapy.

In this model, they assessed inflammation at 48 hours. They easily detected an inflammatory response in a control arm, while very few inflammatory cells were evident in the veins of the animals they treated with gene therapy.

When they assessed intimal thickening, it was appreciable in veins perfused with saline as a control. In contrast, there was a marked reduction in intimal thickening in vein grafts treated with elafin gene therapy (up to 50% in some cases).

The neointima in the vessels treated with elafin might also resist atherosclerotic degeneration, investigators reasoned. Toward this end, they gave animals a high cholesterol diet for 3 months after elafin gene therapy and interposition of vein grafts. In control vessels, they found dense accumulation of lipid, while vessels from the gene therapy arm had only about 50% as much accumulation.

Further research in mice suggested that propensity to develop vascular disease is partially dependent on an individual's ability to mount an anti-elastase response, perhaps by generating elastase inhibitors such as elafin endogenously.

In an experimental model of pulmonary hypertension, the investigators demonstrated that elastase inhibitor therapy, using 2 oral products developed by a pharmaceutical company, provided a survival advantage at 1 and 2 weeks in mice that they treated. Then they measured levels of pulmonary artery pressure and found regression of pulmonary hypertension in comparison with controls.

Because this model suggested that elastase inhibitors could prevent or even reverse vascular disease resulting from inflammation, they evaluated the effect of these agents in the inflammatory process in myocardium. In a mouse model of myocarditis, untreated animals had extensive inflammatory cell infiltration, and even calcification. Mice who received continuous elastase inhibitor therapy showed little evidence of inflammation.

In further observations, they found that treatment of a myocardial infarct model suggested improved healing of heart tissue. More recently, investigators found that elastase inhibitors improve structural and functional healing following myocardial infarction, probably by repressing inflammation and fibrosis.

These study results represent the findings of only one research group. It is the contributions of other research groups, along with this one, that will create a more complete picture of the potential role of elastase inhibitors in vascular disease, Dr. Rabinovitch said.