Chimeric Autologous Vaccine against PCSK9

Excessive expression of protein PCSK9 and its binding to the LDL-receptor leads to the development of hypercholesterolemia and consequent atherosclerosis. The latter is one of the most common causes of morbidity worldwide as it leads to the development of coronary artery disease, cerebrovascular disease and peripheral arterial disease. Since PCSK9’s loss-of-function mutations do not confer any detrimental side effects, PCSK9 represents a natural target for therapeutic approaches towards lowering serum cholesterol and preventing atherosclerosis. Our main objective is to design and develop an innovative vaccine against PCSK9, a chimeric protein, presenting relevant solvent accessible amino acids of the native PCSK9 as the B cell epitopes and thus eliciting humoral immune response. Our goal is to induce formation of neutralizing antibodies, able to bind to both circulating PCSK9 as well as PCSK9 in liver and prevent its binding to the receptor. At the same time, this vaccine should avoid formation of cytotoxic T-lymphocytes against PCSK9 to evade autoimmune destruction of own cells. By directed and precise in silico design of the chimeric protein, we want to generate antibody epitopes in the absence of autoreactive T-cells, which should provide a safe and efficient way of inhibiting the native protein. Furthermore, we also planing to develop an efficient delivery method of the vaccine, using microfluidic preparation of lipid nanoparticles, encapsulating mRNA coding for the chimeric PCSK9. We plan to test vaccine efficacy in vivo, in a mouse model, demonstrating formation of neutralizing antibodies and their action manifested by lowering cholesterol level and preventing development of atherosclerotic lesions. By performing control experiments in clinical blood samples obtained from patients treated for hypercholesterolemia with approved monoclonal antibodies (Alirocumab, Evolucomab), we aim to set standards which the potential anti-PCSK9 vaccine should meet. The project will provide proof-of-concept results as a new safe and efficient therapeutic approach towards treating hypercholesterolemia and preventing atherosclerosis, and the same concept could be used for other therapeutic targets and diseases.