BioWorld International Correspondent

LONDON - A desirable new class of drugs capable of dissolving clots efficiently without increasing the risk of bleeding could be available within 10 years, says an international team of researchers. Experiments with knockout mice have pinpointed a little-known molecule called Gas6 as an ideal target for drugs that would block thrombosis much more safely than those currently available.

Peter Carmeliet, professor of medicine at Flanders Interuniversity Institute for Biotechnology in Leuven, Belgium, told BioWorld International: "We have found that Gas6 acts as an amplifier of the molecules that normally induce platelet aggregation, but that it does not play a role under normal conditions." This is why, he said, blocking Gas6 helps to reduce the tendency of the blood to clot in disease conditions, without increasing the risk of bleeding.

Carmeliet, who is based at The Center for Transgene Technology and Gene Therapy in Leuven, together with colleagues in Malmo, Sweden; Toulouse, France; and London reports the team's results in a paper in the February 2001 Nature Medicine titled, "Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis."

The team already has had informal discussions with a few biotechnology companies about developing the work.

A further study of humans who have experienced thrombotic events is under way to find out whether they have increased levels of Gas6, or of molecules in the same pathway. Carmeliet said, "We want to develop other molecules that inhibit Gas6 and see whether we can bring them from the bench to the bedside. There is still a huge need for drugs that are efficient in working against thrombus formation but which are safe to use. To find a drug that is both efficient and safe is rare."

The team will also try to dissect the molecular pathways by which Gas6 amplifies platelet aggregation.

Gas6 is the name of the protein encoded by the growth arrest specific gene 6. Carmeliet told BioWorld International, "When we started this project, the literature on the role of Gas6 in thrombosis was almost nonexistent. There had been just a few papers reporting that gas6 had been detected in platelets but there was no evidence about its function." He and his colleagues made knockout mice lacking the gene for gas6 but they appeared to be completely normal under baseline conditions. They had no spontaneous bleeding or other hemostatic abnormalities.

Even though Gas6 was not thought to have a role in hemostasis, the team decided to test its role in thrombosis. "That's when my postdoctoral fellow, Anne Angellilo, saw the difference," Carmeliet said. "When we challenged the knockout mice with models of arterial or venous thrombosis, we observed that they were significantly protected. But the beauty is that the deficiency of Gas6, whether by gene inactivation in knockout mice or by neutralization using antibodies to Gas6, does not lead to bleeding." This is quite different, he said, from other knockout mouse models that are protected from thrombosis, but also suffer serious bleeding problems.

It seems, he added, that Gas6 is redundant for normal physiological control of hemostasis, but is an "essential player" in pathological conditions involving thrombus formation.

The team showed that the knockout mice had normal hemostasis using a standard test involving cutting the animals' tails. The volume of bleeding and length of time before clotting occurred was normal. Levels of coagulation factors in the animals' plasma were also normal. Other experiments showed that the knockout animals were significantly less likely to develop clots under circumstances when these would normally occur.

Carmeliet and his colleagues then set out to discover the mechanism by which Gas6 had its protective effect. "When a blood vessel is damaged and a clot is needed, various molecules such as ADP and thrombin are set free and the process of platelet aggregation begins," he said. "Initially, these aggregates are small and labile but in order to form a strong, large clot there needs to be a process of amplification. We believe that these molecules trigger the release of Gas6 from the platelet granules, and that Gas6 acts on its receptor on the platelet surface and in this way somehow signals to amplify the clotting process."

What is surprising, he added, is that Gas6 plays such an important role even though it only acts as an amplifier. "The beauty of it is that because it is only involved in amplification, it is not involved in normal hemostasis - and that is why it is safe to use antagonists against this molecule. Such drugs might have a high therapeutic potency, yet also have a broad therapeutic safety window."