Research Center for Human Genetics at Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1825 Pressler St., Houston, TX 77030, USA.
Research Center for Precision Biomedicine at Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, 1825 Pressler St., Houston, TX 77030, USA.
Int J Mol Sci. 2018 Feb 24;19(2):640. doi: 10.3390/ijms19020640.
PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed. The authors used the scrambled disulfide bond technique to generate conformationally-altered isomers of the catalytic domain of mouse PCSK9. The focus was on the immune response of four X-isomers and their effects on plasma cholesterol and triglyceride levels in both C57BL/6J and Apoe-/- mice. The authors showed that the four immunogens produced significant immunogenicity against native PCSK9 to day 120 after immunization of C57BL/6J and Apoe-/- mice. This resulted in significantly decreased plasma cholesterol levels in C57BL/6J mice, and to a lesser degree in Apoe-/- mice. The X-PCSK9-B1 treated mice had increased LDL receptor mRNA and protein levels at day 120 after treatment. Thus, this study provides a new, potentially promising approach that uses long-term immunotherapy for a treatment of hypercholesterolemia.
前蛋白转化酶枯草溶菌素 9（PCSK9）通过促进 LDL 受体降解来增加血浆胆固醇水平。目前的抗体抑制剂阻断了 PCSK9 与 LDL 受体的相互作用，显著降低了血浆胆固醇水平，并带来了有益的临床效果。为了降低血浆中 PCSK9 的作用，提出了一种新的策略，即产生一系列非天然的、构象改变的 PCSK9 异构体（X-PCSK9），以开发针对天然 PCSK9 的主动免疫疗法，并抑制/阻断 PCSK9 与 LDL 受体的相互作用，从而降低血浆胆固醇水平。作者使用错配二硫键技术生成了小鼠 PCSK9 催化结构域的构象改变异构体。研究重点是四种 X-异构体的免疫反应及其对 C57BL/6J 和 Apoe-/- 小鼠血浆胆固醇和甘油三酯水平的影响。作者表明，这四种免疫原在 C57BL/6J 和 Apoe-/- 小鼠免疫接种 120 天后对天然 PCSK9 产生了显著的免疫原性。这导致 C57BL/6J 小鼠的血浆胆固醇水平显著降低，而 Apoe-/- 小鼠的降低程度较小。X-PCSK9-B1 治疗的小鼠在治疗 120 天后 LDL 受体 mRNA 和蛋白水平增加。因此，这项研究提供了一种新的、有潜力的方法，即使用长期免疫疗法治疗高胆固醇血症。
