The first vaccine against atherosclerosis is not far away in the future, according to Jan Nilsson, professor of Experimental Cardiology at Lunds Universitet in Malmö (Sweden) and EVGN member. Human clinical trials are likely to begin at the end of next year: they will be aimed at verifying the safety of a preparation, still under investigation in a laboratory model, made of antibodies obtained against selected fragments of oxidized Low Density Lipoproteins, or oxLDLs. LDLs are the major component of the “bad cholesterol”: their accumulation in the arterial wall causes inflammation and is a key factor in the onset of atherosclerosis.
The ability of oxidized LDL to trigger an immune response in the body was recognized a decade ago. Studies revealed that these particles can induce an autoimmune response: a response of the body against itself. But they also revealed that the immunization with oxLDL particles reduces the development of atherosclerosis hampering the deposition of atherosclerotic plaques. “Early as they were, these data prompted the scientists to consider vaccination as a feasible option not only for infectious diseases but also for atherosclerosis. And recent evidence confirming the involvement of the immune system in cardiovascular disease has strengthened the idea” says Nilsson, who has a long standing experience in studying atherosclerosis and the immune system.
Setting up a vaccine is not easy: the mechanism of action of the compounds is often unknown, and the reactions in a human being could be different from those observed in a laboratory model. Besides, not all the parts (or epitopes) of an immunogenic molecule trigger the same immune response. “We knew that oxidation alters the external structure of LDLs, but didn’t know which epitope was the most effective. So we tested several fragments (peptides) derived from the protein that stick on the surface of LDLs (apoB100), alone and in combination, to determine their efficacy on atherosclerosis”. What the scientists found was that a single fragment, and not the mix, exerted the strongest effect on the inflammation that surrounds the atherosclerotic plaques. “The injection of this fragment (a procedure called active immunization) triggered the production of antibodies, which determined the reduction of the atherosclerotic lesions up to 70% and the stabilization/regression of the plaques”.
These results induced the scientists to speculate that the direct administration (passive immunization) of an antibody against ApoB100 could be effective as well. So Nilsson and his team developed human antibodies with high affinity for apoB100 fragments, and proved that they can significantly reduce the atherosclerosis in a mouse model.
But what could happen in a human being? The mechanism of action of these antibodies is still unclear, and uncertainties remain on the activation of unwanted inflammatory responses. “We are aware that some points still need to be clarified. However, we expect to obtain the answers within a year, before moving into man” admits Nilsson.
Today, the most common treatment for atherosclerosis are statins. Unfortunately, these drugs do not directly affect oxLDLs, and a high percentage of patients who are treated with statins may still undergo a heart attack or stroke. The research strategy pursued by Nilsson and colleagues could therefore benefit high-risk individuals for whom the conventional treatments do not provide adequate protection.
The European Vascular Genomics Network (EVGN) is the first Network of excellence on cardiovascular disease funded by the European Commission under the 6th Framework Programme "Life sciences, genomics and biotechnology for health" (Contract Number: LSHM-CT-2003-503254).
The Conference is supported by an unrestricted educational grant from Laboratoires SERVIER.
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