Dr Hans Princen
- Metabolic Health Research
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The study, which is published this week in the European Heart Journal, is the first to show that it is possible to immunise genetically modified mice with a molecule that causes the body to produce antibodies against an enzyme called PCSK9 (Proprotein convertase subtilisin/kexin type 9), which plays a role in preventing the clearance of low density lipoprotein cholesterol (“bad” cholesterol) from the blood.
People with high levels of LDL cholesterol, either due to their genetic inheritance, or to poor diet and lifestyles, are at much greater risk of developing cardiovascular disease prematurely. These diseases of the heart and blood vessels, caused by atherosclerosis, have overtaken infections as the main cause of illness and death throughout the world. At present, drugs such as statins can be used to lower LDL cholesterol, but they have to be taken on a daily basis and although they are generally well-tolerated they can cause adverse side effects in some people. The most recently approved cholesterol-lowering compounds are monoclonal antibodies targeting PCSK9, which are highly effective, but their effect is short-lived, resulting in frequent re-application and high costs.
The published research shows that the AT04A vaccine, when injected under the skin in mice that have been fed fatty, Western-style food in order to induce high cholesterol and the development of atherosclerosis, reduced the total amount of cholesterol by 53%, shrank atherosclerotic damage to blood vessels by 64%, and reduced biological markers of blood vessel inflammation by 21-28%, compared to unvaccinated mice. Furthermore, the induced antibodies remained functional over the whole study period and concentrations were still high at the end of the study.
The study was performed with genetically modified mice: the APOE*3-Leiden.CETP mouse. This mouse is developed by TNO and the LUMC to investigate processes related to development of hyperlipidemia and atherosclerosis and was shown to be a predictive and translational animal model to study the efficacy and safety of human drugs.
Dr Günther Staffler, chief technology officer at AFFiRis (the company that developed the AT04A vaccine) and one of the authors of the study, said: “If these findings translate successfully into humans, this could mean that, as the induced antibodies persist for months after a vaccination, we could develop a long-lasting therapy that, after the first vaccination, just needs an annual booster. This would result in an effective and more convenient treatment for patients, as well as higher patient compliance.”