By Debbie Strickland

A team of Midwestern scientists and a Princeton, N.J.-based biotechnology executive have formed CardioGene Therapeutics Inc. to commercialize their cardiovascular research, which includes a clever way to use oral acyclovir, a common herpes antiviral drug, to treat restenosis, or re-occlusion of blood vessels following angioplasty.

The treatment, now in advanced preclinical studies, combines targeted gene therapy delivered via an adenoviral vector with a new kind of catheter to make the smooth muscle cells causing the blockage to express a protein characteristic to herpes simplex-infected cells. The protein — thymidine kinase (tk) — is what makes acyclovir deadly to herpes-infected cells. Acyclovir thus can clear tk-gene-treated vascular roadblocks without harming other cells in the body.

"It's a nice example of how we can combine conventional pharmaceuticals with gene therapy delivery systems," said Gary Nabel, one of CardioGene's cofounders.

The company is pursuing a second, cytostatic gene therapy treatment for restenosis. It involves catheter delivery of the vectors for retinoblastoma, p21 or p27, which prevent the growth of smooth muscle cells that may lead to restenosis.

One of these gene therapies for restenosis could enter clinical trials within two years, if the Princeton, N.J.-based company finds adequate funding, said its sole employee, cofounder Martin Cleary, who has been appointed president and CEO.

Cleary, whose base in New Jersey made the Garden State the company's temporary home, has run several biotechnology firms, in addition to working 14 years at Johnson & Johnson, of New Brunswick, N.J.

Cleary's highest business priority is signing up a partner to support preclinical and clinical development of CardioGene's intellectual property, which consists of one issued patent and 11 patent applications (all U.S.) covering gene, vector and device technologies.

The company's strategy is to ink at least one collaboration deal before seeking equity and venture capital investors, Cleary told BioWorld Today.

Once the financial foundation is firm, CardioGene will relocate to Ann Arbor, Mich. and operate as a full-fledged research and development company. The company's focus will depend to some extent on the kind of partner or partners it attracts.

Although restenosis is CardioGene's initial target, the company's technology has many potential applications, including congestive heart failure, arrhythmia and angiogenesis, according to its founders.

"Over the long term," said Cleary, "our effort will look to address many other cardiovascular conditions using our core gene therapy and delivery technologies."

CardioGene was created in 1996 by scientists Gary and Elizabeth Nabel, of the University of Michigan, in Ann Arbor, and Jeffrey Leiden, of the University of Chicago (formerly of the University of Michigan). To date, the company has raised about $500,000 in cash and in-kind contributions.

On Jan. 1, Cleary reported to work and the company began actively negotiating licensing agreements with the universities and with Vical Inc., of San Diego, which had licensed the Nabels' University of Michigan patent for the catheter.

CardioGene this week licensed from the University of Chicago the final component of its restenosis-centered cardiovascular gene therapy program, inventions of Leiden and Mike Parmacek to enable gene transfer to the vascular smooth muscle cells and a promoter for smooth muscle cell expression.

With annual U.S. spending of $2.4 billion for repeat angioplasty, the restenosis field has attracted plenty of biotechnology competitors, including Centocor Inc., of Malvern, Pa., and ReoPro; NeoRx Corp., of Seattle, and Biostent; Seragen Inc., of Hopkinton, Mass., and DAB389EGF; AntiVirals Inc., of Corvallis, Ore., and a Neu-gene-based candidate; and NitroMed Inc., of Boston, and a nitrogen oxide-based therapy.

"We've looked at the competitive landscape for restenosis," said Cleary, "and it is impressive."

He noted that the founding scientists already have done much of the preclinical lab work at their universities in rats, rabbits and pigs. The studies, Cleary said, "show considerable reduction in cell proliferation and reduction in rates of restenosis."

CardioGene's core technology has been in the making for some 10 years and grew out of the Nabels' marriage of his specialty in molecular virology and her expertise in interventional, molecular and vascular cardiology.

A Marriage Of Technologies

"It occurred to us," said Gary Nabel, "that some viruses used in the laboratory might be applied to the treatment of cardiovascular disease, but the real question was, 'How do you get them to the site of disease in the artery?'

"From the cardiologist's perspective, that's really not a problem — you reach the site with a device. So we thought that the marriage of technologies might allow us to do something that neither could do alone."

With the patented catheter, which creates a protected space for gene delivery, the Nabels have, Cleary said, "overcome one of the limitations that gene therapy companies have faced in developing therapies for cardiovascular disease."

"It's an enabling patent," he added, "meaning that we believe no one else can practice that invention."

In addition to its catheter delivery projects, CardioGene also is working on a gene-delivery system for patients receiving a stent during balloon angioplasty. The treatment involves coating the outside surface of a metallic stent with a genetic compound. The DNA-coated stent treats the major complication of stent-restenosis — the growth of cells through the stent into the vessel wall. *