By Jennifer Van Brunt

Editor

The earliest clinical trial results of a radical new method of treatingcardiovascular disease have not only demonstrated that the technique issafe -- a critical parameter -- but they also indicate that it may be efficacious.For the first time, the theoretical promise of using gene therapy to treatserious heart problems -- including peripheral vascular disease and coronaryartery disease -- has gained a practical footing. In a report to cardiologistsattending last month's annual meeting of the American Heart Associationin Dallas, gene therapy pioneer Ronald Crystal presented initial findingsof a Phase I gene therapy clinical trial in patients scheduled for coronaryartery bypass graft surgery. In this trial, being conducted by Crystaland his associates at New York Hospital-Cornell Medical Center in New York,the patients were treated with an adenoviral vector containing the genefor vascular endothelial growth factor (VEGF 121), which in animal modelshas been able to induce the formation of new blood vessels in tissues withinadequate blood flow. If the gene therapy works in humans, it could bethe means to circumvent coronary blockages by inducing the body to createits own bypasses. For many heart patients, this procedure could then offera new alternative to bypass surgery or balloon angioplasty. For interventionalcardiologists and thoracic surgeons, gene therapy could open up new therapeuticvistas. And for the various companies that have chosen to pursue gene therapyapproaches to treating cardiovascular disease, the huge patient populationsinvolved guarantee significant sales and profits. In the U.S., estimatesrange from 100,000 to 1 million individuals with peripheral vascular disease,at least 250,000 more who are not good candidates for bypass or angiopastysurgeries, along with a significant percentage of diabetics who sufferfrom circulatory problems in their limbs.

There's a vast effort under way -- by academic and industrial researchersalike -- to develop an effective gene therapy for the many facets of heartdisease. And while it is beyond the scope of this article to cover themall, two companies, in particular, have made the news lately with reportsof early clinical trials.

GenVec's Approach

Cornell researcher Crystal's current work is supported by privatelyheld GenVec Inc. and its major partner, Parke-Davis, the pharmaceuticalresearch division of Morris Plains, N.J.-based Warner-Lambert Co.In fact, GenVec, based in Rockville, Md., was actually founded around Crystal'sgene therapy methods, which in 1993 centered on delivering the CFTR gene(cystic fibrosis transmembrane conductance regulator) in an aerosolizedform to the lungs of patients with cystic fibrosis.

But, though GenVec has a number of research programs under way -- includingthe clinical program in cystic fibrosis and another in colon cancer andliver metastasis -- it's the cardiovascular field that's taken center stage,spurred by Parke-Davis' $100 million commitment to the program in Sept.1997. In that deal, which spans a five-year period, Parke-Davis gets marketingrights worldwide, except Asia, to the cardiovascular gene therapy now inthe clinic as well as related therapeutic angiogenesis products. GenVecgets royalties -- which could be substantial -- and certain manufacturingand co-promotion rights.

GenVec's current approach involves the delivery of the VEGF 121 genein a modified, replication-deficient adenoviral vector, directly into theheart muscle cells by injection.

There are actually two arms to the Phase I trials now underway in NewYork, explained GenVec's president and CEO Paul Fischer. The firstis a dose-escalation study in 15 patients with severe coronary diseasewho are scheduled for coronary artery bypass graft surgery (CABG). Butthere are areas in these individuals' hearts where CABG can't be done --and that's where the gene therapy is employed.

"This patient population represents a good group in which to assesssafety," Fischer explained, "because the gene therapy procedure would minimizerisk to the patient." And, in fact, the results so far have demonstratedthat there is no evidence of toxicity related to either the vector or thegene. "In addition, extensive analyses of cardiac function [by the usualmeasurements] demonstrated no evidence of effects that could be attributedto the vector or the gene," Fischer added.

The second arm of the clinical study involves six patients with severecoronary artery disease who are not candidates for surgery. (Accordingto Fischer, there about about 75,000 individuals in the U.S. who fall intothis category.) In this case, they will receive the gene therapy via minimallyinvasive surgery. Here again, Fischer said, the vector and the gene appearto be safe.

Taken together, these studies have used very small numbers of patients,but they are encouraging enough to warrant larger Phase II studies, Fischerexplained.

What the results don't show is whether these patients have formed newcollateral blood vessels as a result of the gene therapy. In fact, becauseany new vessels will be tiny, they are probably too small to detect inan angiogram. But angiograms, which are given 30 days after the therapy,do demonstrate improved blood flow. "What we probably see is the abilityof these smaller vessels to contribute to improved blood flow, which allowsthe larger vessels to fill better, which is picked up in the angiogram,"he said.

One has to turn to animal experiments to prove that treatment with theVEGF gene results in the formation of new blood vessels. In the rat, forinstance, one can detect the formation of new capillaries within severaldays. They continue to grow for about three weeks to a month and then stabilize.The same timetable has been demonstrated in the pig model, where the animals'hearts have been completely restored to normal function at 30 days. Inboth animal systems, the VEGF gene is expressed for about a month. Butthat's a sufficient amount of time for the gene to induce the cascade ofevents that lead to normalcy.

If the technique proves out in humans, then it will fall to the physicians-- the thoracic surgeons and interventional cardiologists -- to pick thepatients who will benefit most from the new procedure.

Collateral's Non-Surgical Approach

While GenVec's current research centers on a surgical means of deliveringthe putative therapeutic gene to heart patients, Collateral TherapeuticsInc. emphasizes a non-surgical approach to gene therapy for heart disease.The San Diego company's (NASDAQ:CLTX) gene therapy is also in patients;in May 1998, its corporate collaborator Berlex Laboratories Inc., a Wayne,N.J., subsidiary of German pharmaceutical giant Schering AG, initiatedU.S. Phase I/II trials in patients with chronic stable exertional anginadue to atherosclerosis. Not only is this a different patient populationthan GenVec's, but also Collateral is using a different gene and deliverymethod. Collateral's product, called GeneRx, consists of the fibroblastgrowth factor-4 gene (FGF-4) in an adenoviral vector; it is delivered tothe heart during a diagnostic angiogram, a non-surgical procedure. Butthe similarity comes from the fact that the FGF gene -- like the VEGF gene-- stimulates angiogenesis. The ultimate goal is the same -- to createan alternate route for blood to bypass clogged arteries in the heart andto perhaps alleviate the need for surgery or lifelong drug therapy.

With this product, explained Collateral's chief operating and financialofficer Christopher Reinhard, the "goal is non-surgical delivery[of the gene therapy] on a one-time basis....The treatment is performedby an interventional cardiologist at the time of diagnosis." The companyhas yet to report any results, but has found from preclinical experimentsthat one-time administration of the gene is enough to initiate the developmentof the new blood vessels.

In August of this year, Collateral was awarded a U.S. patent on itstechnology, bolstering its proprietary position. The patent, on gene-transfermediated angiogenesis therapy, is directed to the non-surgical administrationof angiogenic genes for treating coronary artery disease and peripheralvascular disease. The patented technology forms the basis of the productnow in the clinic.

But Collateral has a portfolio of genes at its disposal, including VEGF,and plans for each in different areas of heart disease. The first, however,may be the most lucrative: According to Collateral's Reinhard, there areclose to 14 million individuals in the U.S. with coronary artery disease.Of those, about 7.2 million have angina.

Evolution

Heart disease is a far cry from a rare genetic disorder, however, andthe fact that researchers today are delving into such widespread applicationsfor gene therapy demonstrates just how far scientific thinking has evolvedin the last decade.

It's now been more than eight years since the first therapeutic humangene therapy procedure was performed. That clinical trial, in which a younggirl suffering from severe combined immunodeficiency received an injectionof lymphocytes transfected with the human gene for adenosine deaminase,was deemed a success.

It's not surprising, then, that in the beginning, the highest hopesfor gene therapy came from its theoretical ability to replace a defectivegene with a healthy one. But the focus has shifted substantially sincethen. Though there are still efforts underway to devise gene therapy approachesto treating genetic flaws, there's been increasing emphasis on treatmentsfor cancer and AIDS in recent years. And now, the mix has changed onceagain, to include cardiovascular disease. *