By David N. Leff

Every home buyer and loan applicant knows the meaning of the word "collateral." It's security posted to protect the bank or seller against default.

That's collateral in the singular. Collaterals — plural — have a different meaning for cardiologists and oncologists. Collaterals are new blood vessels that branch out from existing veins and arteries. Malignant tumors depend on collaterals to supply them with the flow of blood-borne nutrients they need to grow. Much anticancer effort goes into preventing this angiogenesis. Strategies involve inhibiting the growth-factor genes that trigger production of the endothelial cells that make up the inner walls of blood vessels.

Cardiologists wear a different hat. Their aim is to restore blood flow to a heart gasping for oxygen, as by balloon angioplasty, which reams out coronary arteries blocked by atherotic plaque. When this fails, cardiovascular surgeons practice a rough-and-ready form of angiogenesis, grafting veins from elsewhere in the body as hand-made collaterals, to bypass the occluded arteries.

Half a million coronary artery bypass operations take place each year in the U.S. and 400,000 angioplasties. Both approaches — surgical and non-surgical — burst into the news this week via a news release and a press conference.

Journalists from some 30 print and TV media crowded into a room at Cornell University Medical College, in New York, to hear gene therapy pioneer Ronald Crystal confirm a rumor that had been circulating in cardiac circles for a fortnight.

On December 17, he announced, a 60-year-old man with severe coronary artery disease received 10 injections into his open heart during bypass surgery at Cornell. The gene-therapy treatment consisted of genes expressing vascular endothelial growth factor (VEGF) delivered by a disarmed adenovirus vector.

"In this particular patient," Crystal said, "his right coronary artery was totally occluded; there was no area in it we could bypass to. Using an insulin syringe, we injected directly into the myocardium in 10 separate areas, covering about 30 square centimeters. The whole procedure for the gene therapy took eight minutes."

Simultaneously, a closely held company in La Jolla, Calif., released a press statement headed: "Collateral Therapeutics announces details of first commercial IND [investigational new drug] filing for revolutionary new, non-surgical gene- therapy treatment for coronary artery disease."

Collateral Seeks Quick IND To Market

Unless the FDA objects within 30 days, the firm's chief operating and financial officer, Christopher Reinhard, told BioWorld Today, "We plan to start a placebo-controlled Phase I/II clinical study of actual patients with stable exertional angina pectoris." He added, "They will be getting an intra-arterial injection of an adenovirus vector, delivering genes for fibroblast growth factor [FGF].

"As opposed to Cornell's cardiothorascic surgery, done in a bypass environment," Reinhard pointed out, "ours is a non-surgical approach."

An interventional cardiologist, he explained, while performing a diagnostic angiogram, will thread a slender catheter through a femoral artery into a coronary artery and deliver the gene-therapy package well inside the heart muscle.

"It's not an injection into the myocardium," he continued, "but into the coronary artery, from which the heart picks it up. There, the viral vector transfects heart cells with the growth factor gene, which expresses a protein that stimulates the growth of collateral vessels."

The company's vice president and medical director, Robert Engler, recalled that "peer-reviewed studies in a well-defined preclinical animal model show that Collateral's proprietary gene therapy treatment can consistently restore myocardial blood flow and heart function. We look forward to translating the success of this program into humans."

That translation to clinical trials, beginning in February, will enroll "between 50 and 60 patients," Reinhard said, "at 10 cardiovascular centers across the U.S."

The preclinical studies to which Engler alluded featured 50 to 70 100-pound domestic pigs (Sus scrofa) at the University of California-San Diego. Nature Medicine for May 1996 reported this porcine trial in an article titled: "Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart."

Although pigs don't develop coronary artery disease," Reinhard observed, "they do grow collateral vessels in response to a blockage. The viral vector with our gene achieved full and complete blood flow and function in every one of our animals."

The interval between the gene therapy injection and this positive outcome was two weeks, Reinhard recounted, and that is the period of angiogenesis anticipated in the impending human trials. "In our pigs, the heart developed additional supplemental collateral vessels of various sizes," he recounted, "which then brought blood into the ischemic area of the heart."

Cornell has conducted comparable pig trials, about to be reported in the January issue of the Journal of Thoracic and Cardiovascular Surgery. "These are large animals that have occlusion of their circumflex and coronary arteries," Crystal told BioWorld Today, adding, "The data are spectacular. We administered the viral vector with the VEGF gene and a month later the pigs had essential normalization of their angiogram, echocardiography of the wall of the heart with stress, and also nuclear medicine studies of blood flow with stress."

Cornell Expanding Clinical Trials

He made the point that "the data in the animal model were so dramatic, in terms of efficacy, that it was one reason we moved to humans so quickly."

He and the Cornell surgeons are now projecting, Crystal said, "the first 15 patients of our Phase I trial, combining the gene therapy with open-chest conventional cardiac bypass surgery. We intend to enroll one new subject every two weeks, starting up in another week or so."

As for the outcome of that first patient, "It's going to take another eight months or so before we have enough data to be able to say anything."

Crystal does not denigrate Collateral's non-surgical approach. All of the strategies we and others are exploring," he went on, "are, I think viable alternatives — including the Collateral Therapeutics one. It may be that for different patient populations you would choose different approaches."

Reinhard concluded, "We and Cornell are both trying to work on the same therapeutic approach, and I think we're all pleased that angiogenesis is finally becoming more mainstream." *