Active Immunity Targeted at PCSK9 for the Treatment of Hypercholesterolemia

针对 PCSK9 的主动免疫治疗高胆固醇血症

• 批准号: 8191302
• 负责人: BA-BIE TENG
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-22 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191302
• 关键词: Active Immunotherapy; Active immunity; Aftercare; Amino Acids; Antibodies; Antigens; Apolipoprotein E; Apolipoproteins B; Arterial Fatty Streak; Atherosclerosis; Back; Binding; Biological Assay; C57BL/6 Mouse; Cardiovascular Diseases; Catalytic Domain; Cell surface; Cells; Cholesterol; Clinical; Cysteine; Development; Disease; Disulfides; Enzyme-Linked Immunosorbent Assay; Genes; Genetic Transcription; Goals; Human; Immune; Immune Tolerance; Immune response; Immune system; Isomerism; LDL Cholesterol Lipoproteins; Laboratories; Lead; Length; Life; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Lysosomes; Measures; Mediating; Methods; Molecular Chaperones; Mus; Operative Surgical Procedures; Patients; Peptides; Pharmaceutical Preparations; Plasma; Process; Proprotein Convertases; Protein Region; Proteins; Recycling; Subtilisins; Techniques; Therapeutic; Toxic effect; Vaccination; Vaccines; Vascular Endothelial Growth Factors; Work; cardiovascular risk factor; design; disulfide bond; gene discovery; hypercholesterolemia; immunogenicity; in vivo; inhibitor/antagonist; kexin; new technology; new therapeutic target; novel strategies; novel therapeutics; oxidized low density lipoprotein; success; therapeutic vaccine; uptake; vaccine development

DESCRIPTION (provided by applicant): The long-term objective of this proposal is to design and develop novel strategies to inhibit/reduce PCSK9 action. This is a potential powerful new therapeutic target to regulate LDL cholesterol and reduce the burden of cardiovascular disease. PCSK9 (Proprotein convertase subtilisin/kexin type 9) is a newly discovered gene that has a profound effect on LDL cholesterol levels by binding to LDL receptor and acts as a chaperon, mediates LDL receptor to lysosome for degradation. Studies in Humans demonstrated that total PCSK9 deficiency had very low LDL cholesterol (14-16 mg/dl) with no adverse clinical consequences. Thus, PCSK9 would be an excellent target for the treatment of hypercholesterolemia. Moreover, it has been shown that statins increase PCSK9 transcription, resulting in higher plasma PCSK9 levels. Then, a combination treatment of statins and PCSK9 inhibitor(s) would provide a better therapy to reduce LDL cholesterol. In this application, we propose to use an active immunotherapy strategy by generating a vaccine that stimulates the immune system against PCSK9. Proteins are unique bio-molecules, they unfold and refold, generate a mixture of diverse conformational isomers. We developed a technique of disulfide scrambling permits reversible conversion between the native and diverse denatured isomers. Our preliminary results have shown that these isomers induced immunogenicity towards native protein and decreased plasma cholesterol levels. This is a novel approach to use disulfide scrambling to generate conformational isomers of Pcsk9 (X- Pcsk9) to induce immunogenicity towards native Pcsk9. This process will block the interaction of PCSK9 and LDL receptor to decrease LDL cholesterol for the treatment of hypercholesterolemia. Moreover, Vaccine for atherosclerosis towards oxidized LDL or apolipoprotein B peptide has shown some success. Thus, the proposal of developing vaccine against PCSK9 to regulate LDL cholesterol is an exciting and feasible approach In this application, we will generate and produce a panel of X-Pcsk9 isomers vaccines, which will cross- react with native Pcsk9. We propose to evaluate the potency of these vaccines on decreasing cholesterol levels as well as modulating atherosclerosis development in vivo. In summary, this study will provide novel therapeutic treatment for decreasing LDL levels and reducing the burden of cardiovascular disease. PUBLIC HEALTH RELEVANCE: Atherosclerosis is one of the leading causes for cardiovascular disease. Most patients suffer from elevated LDL cholesterol. Currently the treatment options for this disease are limited to surgery and life-long therapy on the statin drug, and statin often does not work well for certain patients. Our study seeks to study a new gene PCSK9 and develop novel therapeutics to decrease LDL cholesterol, and to stop and reverse atherosclerosis. The success of this study would lead to the development of clinically applicable therapeutics to modulate LDL and atherosclerosis.

描述（由申请人提供）：该提案的长期目标是设计和制定抑制/减少PCSK9动作的新型策略。这是一个潜在的强大新治疗靶标，可调节LDL胆固醇并减轻心血管疾病的负担。 PCSK9（普罗蛋白转化酶枯草蛋白/Kexin型9）是一个新发现的基因，通过与LDL受体结合而对LDL胆固醇水平产生深远影响，并充当伴侣，将LDL受体介导至溶酶体以降解。在人类中的研究表明，总PCSK9缺乏症的LDL胆固醇（14-16 mg/dl）没有不良临床后果。因此，PCSK9将是治疗高胆固醇血症的绝佳靶标。此外，已经表明他汀类药物会增加PCSK9转录，从而导致较高的等离子PCSK9水平。然后，他汀类药物和PCSK9抑制剂的组合治疗将提供更好的疗法来降低LDL胆固醇。 在此应用中，我们建议通过产生一种刺激针对PCSK9的免疫系统的疫苗来使用主动免疫疗法策略。蛋白质是独特的生物分子，它们展开并重新塑造，产生各种构象异构体的混合物。我们开发了一种二硫键混乱的技术，允许天然和多样的变性异构体之间的可逆转换。我们的初步结果表明，这些异构体诱导了对天然蛋白质的免疫原性，并降低了血浆胆固醇水平。这是一种使用二硫键拼凑来产生PCSK9（X-PCSK9）的构象异构体以诱导天然PCSK9的免疫原性的新方法。该过程将阻止PCSK9和LDL受体的相互作用，以降低LDL胆固醇以治疗高胆固醇血症。此外，针对氧化的LDL或载脂蛋白B肽的动脉粥样硬化疫苗显示出一些成功。因此，针对PCSK9开发疫苗以调节LDL胆固醇的建议是一种令人兴奋且可行的方法，我们将生成并生产一组X-PCSK9异构体疫苗，该疫苗将与本机PCSK9交叉反应。我们建议评估这些疫苗对降低胆固醇水平的效力，并调节体内动脉粥样硬化的发展。总而言之，这项研究将提供新颖的治疗方法，以降低LDL水平并减轻心血管疾病的负担。 公共卫生相关性：动脉粥样硬化是心血管疾病的主要原因之一。大多数患者患LDL胆固醇升高。目前，这种疾病的治疗选择仅限于他汀类药物的手术和终身治疗，而他汀类药物通常对某些患者效果不佳。我们的研究旨在研究一种新的基因PCSK9并开发新的疗法以降低LDL胆固醇，并停止和逆转动脉粥样硬化。这项研究的成功将导致临床适用的治疗剂的发展以调节LDL和动脉粥样硬化。