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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

基本信息

批准号：
8306156
负责人：
BA-BIE TENG
金额：
$ 22.5万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-22 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306156
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

项目摘要

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.

描述(由申请人提供)：这项提案的长期目标是设计和开发新的策略来抑制/减少PCSK9的作用。这是一个潜在的强大的新的治疗靶点，可以调节低密度脂蛋白胆固醇，减轻心血管疾病的负担。PCSK9(Protein Convertase subtilisin/kexin type 9)是一个新发现的基因，它通过与低密度脂蛋白受体结合而对低密度脂蛋白水平产生深刻的影响，并作为伴侣，将低密度脂蛋白受体介导到溶酶体中进行降解。对人类的研究表明，PCSK9总缺乏症的低密度脂蛋白胆固醇非常低(14-16毫克/分升)，没有不良的临床后果。因此，PCSK9将是治疗高胆固醇血症的一个很好的靶点。此外，他汀类药物还能增加PCSK9的转录，导致血浆PCSK9水平升高。那么，他汀类药物和PCSK9抑制剂(S)的联合治疗将为降低低密度脂蛋白提供更好的治疗方法。在这个应用中，我们建议使用一种主动免疫治疗策略，通过产生一种疫苗来刺激针对PCSK9的免疫系统。蛋白质是一种独特的生物分子，它们可以展开和再折叠，产生各种构象异构体的混合物。我们开发了一种二硫化物加扰技术，允许天然异构体和各种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的免疫原性，并降低了血浆胆固醇水平。这是一种新的方法，利用二硫键扰乱产生PCSK9(X-PCSK9)的构象异构体来诱导对天然PCSK9的免疫原性。这一过程将阻断PCSK9和低密度脂蛋白受体的相互作用，从而降低低密度脂蛋白治疗高胆固醇血症。此外，针对氧化型低密度脂蛋白或载脂蛋白B肽的动脉粥样硬化疫苗也取得了一定的成功。因此，开发针对PCSK9的疫苗来调节低密度脂蛋白是一种令人兴奋和可行的方法。在这一应用中，我们将生产和生产一组X-PCSK9异构体疫苗，它将与天然的PCSK9发生交叉反应。我们建议评估这些疫苗在体内降低胆固醇水平和调节动脉粥样硬化发展方面的效力。综上所述，本研究将为降低低密度脂蛋白水平和减轻心血管疾病负担提供新的治疗方法。