A CD&D

A team of researchers at Oregon Health & Science University (OHUSU; Eugene) and Washington University (St. Louis) say they have described for the first time the mechanism that gives a mutant enzyme molecule that they have engineered – and patented – with potential to become a breakthrough drug for treating heart attacks and strokes.

The team said this genetically modified enzyme, WE-thrombin, functions as a potent clot- busting agent while retaining little of the power that thrombin, its non-engineered parent, has in clot-building.

The research report appears in Arteriosclerosis, Thrombosis, and Vascular Biology, a journal of the American Heart Association (Dallas), and an editorial in the issue calls the research "a significant advance in understanding the functions and antithrombotic potential of [WE thrombin] in particular, and the approach of using engineered human proteins more broadly ... "

Development of WE-thrombin "would be a major medical breakthrough in antithrombotic therapy, ultimately saving thousands of lives worldwide each year," said lead investigator Andr s Gruber, MD, PhD, associate professor of medicine in the division of hematology and medical oncology, OHSU School of Medicine, said that the development of WE-thrombin would be "a major breakthrough" in antithrombotic therapy

Thrombin is an enzyme that can both promote and prevent blood clotting, the balance of these two requiring a complex system of positive and negative feedback loops.

The researchers contemplate that, if it is approved for use in humans, WE thrombin – demonstrated by the researchers as effective and safe in large primates – could safely be injected at the first signs of a stroke or heart attack without, in the case of a false alarm, fear of causing harm, a primary barrier in the early use of tPA which can cause harm if used for the wrong applicaiton.

Aronora, a startup biotech formed by Gruber along with the primary co-investigators and others, are seeking funding for preclinical and early clinical development of WE-thrombin as an alternative to existing antithrombotic drugs, a market estimated to exceed $20 billion a year, worldwide. The patents on WE-thrombin are currently co-owned by the investigators' parent institutions, OHSU, Emory University and Washington University.

"WE-thrombin is the most potent antithrombotic agent that ever has been described," said Gruber. "And that's because of its specificity. It effectively utilizes a natural "drug delivery system" of circulating blood platelets and white blood cells that accumulate in the clot formation process to deliver its punch directly to a blood clot. The process parallels that of targeted drug delivery. It's effective inside a blood vessel, but not at all effective outside the blood stream, which is exactly what you want from an antithrombotic agent."

"What we've done recently," said co-investigator Owen McCarty, PhD, assistant professor of biomedical engineering in the department of cell and developmental biology, OHSU School of Medicine, "is located the exact point where the catalytic reaction takes place in vivo that makes this molecule work as a superior antithrombotic agent."

WE-thrombin, the mutant form of thrombin, lacks the ability to create the glue but still can produce activated protein C (APC) inside the blood vessels, which makes it a locally acting anti-coagulant. The molecule enhances this ability, the research team discovered, by attaching itself to a receptor, or sticking point, called glycoprotein Ib (GPIb), located on the surface of platelets. In doing so, WE-thrombin shoulders aside – and thus inhibits – the protein (the von Willebrand factor) that promotes coagulation, which now has to compete for the same receptor on the platelets.

Because of WE-thrombin's specificity and potency, the dosage required to be effective in humans, Gruber said, is expected to be less than 0.5 milligrams, and possibly less than 0.1 milligrams, or 200-fold to 1,000-fold less than the dosage levels of tPA commonly being administered.