By Nancy Volkers

Special To BioWorld Financial Watch

Cardiovascular disease (CVD) is the leading cause of death and disability in industrialized countries. In the U.S., about 59 million people have one or more types of cardiovascular disease, an umbrella term that includes high blood pressure, coronary heart disease, rheumatic fever, congenital defects and congestive heart failure.

This year, the cost of CVD in the United States is pegged at $286.5 billion; this figure includes health expenditures ($178.2 billion) and lost productivity ($108.3 billion). In 1995, the average coronary artery bypass surgery cost $44,820.

Despite its prevalence and cost in terms of both dollars and human health cardiovascular disease is not a hotbed of biotechnology research. Of the more than 300 pivotal trials that took place in 1998, 13 were for cardiovascular disease, compared with 78 for cancer; 30 for infectious diseases; 17 for neurological conditions; 16 for AIDS, and 14 for hepatitis.

Some biotechnology firms are working toward new therapies for cardiovascular disease; of those, a handful are doing so by collaborating with universities.

In April, Variagenics, Inc. acquired exclusive rights to the methylenetetrahydrofolate reductase (MTHFR) gene for diagnostic and therapeutic purposes. Variations in the MTHFR gene have been associated with increased risk of a form of cardiovascular disease. Rights were acquired from McGill University in Montreal.

The product of the MTHFR gene is a folate cofactor, required to turn homocysteine into methionine. Further work at McGill led to the discovery of polymorphisms at a single amino acid. The alanine version of the gene has approximately twice the activity of the valine form. People with two copies of the valine form have high homocysteine levels, compared with other genotypes. Vincent Stanton, vice president of discovery research at Variagenics, said 10 to 12 percent of North Americans are homozygous for the valine form.

"Recently, a number of studies have convincingly demonstrated that elevated homocysteine is a risk factor for cardiovascular disease," Stanton said. He added that having an elevated homocysteine level is now considered a risk factor on par with well-established risk factors such as smoking, diabetes, a family history of CVD and high cholesterol levels.

Though the relationships between MTHFR genotype and homocysteine levels, and between homocysteine levels and CVD, are well established, making the logical jump to the relationship between MTHFR genotype and CVD has been more complicated, Stanton said.

"Some studies show an effect of MTHFR genotype on CVD, but some don't," he said, because "the gene accounts for only some of the variation in homocysteine levels, and similarly, homocysteine levels are only partially predictive of CVD."

Variagenics intends to commercialize tests based on the MTHFR gene for routine clinical use in identifying patients for whom treatment with folate would reduce the risk of cardiovascular disease.

"What lies ahead is to identify the subgroup in whom the MTHFR genotype is a serious contributor to risk of CVD," Stanton said. Members of this subgroup who take supplemental folate on a long-term basis can "significantly reduce their risk of CVD," he added.

The MTHFR gene is also implicated in certain birth defects, such as spina bifida, Stanton said. Though currently women attempting pregnancy are encouraged to take folic acid supplements to reduce the risk of these defects, Stanton said there exists a subgroup of women in which supplementation is more important.

Variagenics has also acquired the thiopurine methyltransferase (TPMT) gene, which the company licensed from the Mayo Foundation. TMPT is a marker for adverse events associated with certain anticancer drugs. The company also licensed the apolipoprotein E (ApoE) gene from Nova Molecular Inc.; ApoE is a marker of patient response to drugs used to treat cognitive disorders, including Alzheimer's Disease.

Founded in 1992 as K.O. Technology, Variagenics is a private, venture-backed company.

In January, another Cambridge-based company announced a cardiovascular collaboration. Genzyme Corp. will collaborate with The Toronto Hospital to develop and commercialize cell-based therapies to treat cardiovascular disease. The research group is led by Richard Weisel, a cardiac surgeon. The initial focus is an autologous transplant procedure, in which cultured cardiomyocytes are transplanted into scar tissue that forms following a heart attack. Currently, there is no therapy to restore function to myocardial scar tissue.

At an April thoracic surgery meeting, Weisel's group presented pre-clinical data on the therapy. Researchers induced myocardial infarction (MI) in adult pigs. In some pigs, healthy cells were removed, cultured, and then injected into the scar tissue following the MI. Controls received an injection of culture medium.

Four weeks post-transplant, the experimental group had improved blood flow, motion and thickening, as well as an increase in ejection fraction, a measure of cardiac function. Controls showed no such improvements. According to an April announcement, Genzyme expects to initiate clinical trials in this area in 2001.

Genzyme acquired rights to all intellectual property and technology relating to existing cardiomyocyte and cell therapy research performed by Weisel and his associates. Genzyme also will solely own, or have access to, all new technology produced by the collaboration. The company will fund all research, development, and commercialization; will pay an up-front fee to acquire the intellectual property and technology rights; and will make milestone and royalty payments.

Bo Piela, manager of public relations at Genzyme, said the company was "looking to exploit that cell therapy expertise in a way that matched the focus of our surgical products business, which focuses on biosurgery bringing biotech into the surgical suite." "That's why the work that Dr. Weisel and colleagues are doing was attractive to us it matched our capabilities and where we wanted to take our surgical products business," Piela said.

Genzyme's surgical products business became its own entity June 28, when its stock begins trading on Nasdaq under the ticker symbol GZSP. Genzyme Surgical Products, created from Genzyme General's existing surgical products business, becomes the fourth division of Genzyme Corp.; the others are Genzyme General (GENZ), Genzyme Tissue Repair (GZTR) and Genzyme Molecular Oncology (GZMO).

Genzyme has existing collaborations with researchers at a number of institutions to develop gene therapy products that augment or supplement established treatments for ischemic heart disease and congestive heart failure. Piela said the company will initiate a clinical trial in cardiovascular gene therapy later this year.

In collaboration with Genzyme Transgenics Corp. (NADSAQ:GZTC), the company is conducting Phase III trials of recombinant human antithrombin III, a transgenic anti-clotting therapeutic with potential use in coronary artery bypass grafting surgery.

Nearly one million people die each year from CVD half of them from coronary heart disease, which affects approximately 12 million people. According to the National Heart, Lung and Blood Institute, one of every two men and one of every three women will eventually develop coronary heart disease.

Many think of CVD as a "man's disease" in fact, males suffer heart attacks an average of 10 years earlier in life than women do. But for all types of CVD combined, mortality rates are higher in women, and have been for the last 15 years. In 1996, there were 505,930 deaths in women; this was 52.7% of all deaths from CVD and more than the next 16 causes of death in women combined. *