In vivo vascular delivery of an MK2 inhibitory peptide for the prevention of smooth muscle cell phenotype switch and intimal hyperplasia.

MK2 抑制肽的体内血管递送可预防平滑肌细胞表型转换和内膜增生。

• 批准号: 10729846
• 负责人: John W Tierney
• 金额: $ 4.77万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729846
• 关键词: Acute; Adverse effects; Affect; Amputation; Angioplasty; Aorta; Arteries; Atherosclerosis; Back; Balloon Angioplasty; Bilateral; Biological Availability; Biological Markers; Bioreactors; Blood Vessels; Blood flow; Bypass; CREB1 gene; Catheters; Cessation of life; Clinical Trials; Complex; Contralateral; Convection; Cytoplasm; Data; Development; Drug Kinetics; Drug Targeting; Drug usage; Electrostatics; Endothelial Cells; Endothelium; Extracellular Matrix; Failure; Family suidae; Formulation; Gene Expression; Genes; Goals; Harvest; High Fat Diet; Histologic; Hour; Human; Hyperplasia; Inflammation; Inflammatory; Infusion procedures; Inhibition of Cell Proliferation; Injections; Injury; Intervention; Kinetics; Label; Lead; Legal patent; Limb structure; Maintenance; Measures; Mechanical Stress; Mechanics; Medial; Methods; Modeling; Operative Surgical Procedures; Oryctolagus cuniculus; Paclitaxel; Pain; Pathologic; Pathologic Processes; Pathway interactions; Patients; Penetration; Peptides; Perfusion; Peripheral; Peripheral arterial disease; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Phase; Phenotype; Phosphorylation; Polymers; Prevention; Process; Production; Proliferating; Quantitative Reverse Transcriptase PCR; RNA; Rattus; Role; Sampling; Saphenous Vein; Signal Pathway; Sirolimus; Site; Smooth Muscle Myocytes; Stents; Stress; Stress Response Signaling; System; Testing; Therapeutic; Therapeutic Effect; Thrombosis; Time; Tissues; Transplantation; Trauma; Vascular Smooth Muscle; Vein graft; Western Blotting; Work; acrylic acid; antiproliferative drugs; artery occlusion; biological adaptation to stress; common treatment; cytokine; druggable target; efficacy testing; iliac artery; improved; in vivo; in vivo Model; in vivo evaluation; inflammatory marker; migration; neointima formation; non-healing wounds; novel; p38 Mitogen Activated Protein Kinase; peptide drug; pharmacokinetics and pharmacodynamics; phenotypic biomarker; porcine model; post-transplant; pressure; prevent; restenosis; standard care; targeted treatment; therapeutically effective; transcriptome sequencing; transplant model; vascular smooth muscle cell proliferation

PROJECT SUMMARY Peripheral artery disease (PAD), an atherosclerotic disease leading to peripheral artery obstruction, affects over 6.5 million people in the US. PAD reduces blood flow, causing limb pain, non-healing wounds, and in extreme cases even death. Percutaneous transluminal angioplasty (PTA), involving inflation of a balloon at the site of blockage to re-open the arterial lumen, is a common treatment for PAD. However, vascular wall stress associated with balloon distension (sometimes in combination with stent placement) damages and activates stress response in the tissue, leading to restenosis, a re-narrowing of the artery. Because of these complications, most PTA-treated vessels fail within the first 12 months. Restenosis is driven by the pathological process intimal hyperplasia (IH), characterized by vascular smooth muscle cells (VSMCs) switching from a contractile to synthetic phenotype, causing them to become more migratory, proliferative, and active in secreting extracellular matrix (ECM) and inflammatory cytokines. Synthetic VSMC activities produce neointima that closes back off the vessel and that serves as a fertile ground for advanced atherosclerosis or even thrombosis. Current therapeutic strategies to reduce IH focus solely on inhibiting VSMC proliferation through the use of drug coated balloons and stents. However, these methods have not shown promise in improving vessel patency in clinical trials. I have been pursuing inhibition of the p38-MK2 “stress response” signaling pathway as a more comprehensive IH therapy that targets the underlying mechanisms that drive the pathological VSMC phenotype switch. In my recent studies, inhibition of MK2 through the use of a novel peptide therapeutic (MK2i) electrostatically complexed with a pH-sensitive endosomolytic polymer to form nanopolyplexes (MK2i-NPs) proved to be promising in the inhibition of VSMC proliferation, phenotype switching, and IH. In the context of vascular bypass grafts, a rabbit vascular transplant model showed that a single intra-operative treatment with MK2i-NPs (topically to explanted tissue) inhibited neointima formation up to 28 days after surgery and mitigated VSMC phenotype switching during the acute (7 day) stress response phase post-transplant. We hypothesize that in vivo, catheter-based delivery of MK2i in conjunction with balloon angioplasty will prevent VSMC phenotype switching and protect against restenosis and vessel failure. To model in vivo delivery from a specialized catheter, I will develop an ex vivo bioreactor system and apply this system to evaluate the effects of pressure on MK2i penetration and retention in the vessel wall. Additionally, we will use the bioreactor to evaluate pharmacokinetics and pharmacodynamics of MK2i in arteries ex vivo. Finally, based on the pressure conditions optimized in initial work, we will apply a specialized occlusion perfusion catheter to create a “chamber” within the lumen of the vessel through which the MK2i-NPs can be controllably administered for convective transfer into the vascular wall in vivo. This system will be deployed in a pig model to assess the effect of in vivo MK2i delivery on maintenance of VSMC contractile phenotype and overall vessel patency following PTA.

项目概要 外周动脉疾病（PAD）是一种导致外周动脉阻塞的动脉粥样硬化性疾病， 影响美国超过 650 万人。 PAD 会减少血流量，导致四肢疼痛、伤口不愈合以及 极端情况下甚至死亡。经皮腔内血管成形术 (PTA)，涉及在 在堵塞部位重新打开动脉管腔，是 PAD 的常见治疗方法。然而，血管壁应力 与球囊扩张（有时与支架置入相结合）相关的损伤和激活 组织中的应激反应，导致再狭窄，即动脉重新变窄。由于这些并发症， 大多数经过 PTA 处理的血管会在前 12 个月内失效。再狭窄是由内膜病理过程驱动的 增生（IH），其特征是血管平滑肌细胞（VSMC）从收缩型转变为 合成表型，使它们变得更具迁移性、增殖性和分泌细胞外液的活性 基质（ECM）和炎症细胞因子。合成 VSMC 活动会产生新内膜，从而关闭血管 血管，是晚期动脉粥样硬化甚至血栓形成的沃土。目前治疗 减少 IH 的策略仅集中于通过使用药物涂层球囊来抑制 VSMC 增殖， 支架。然而，这些方法在临床试验中并未显示出改善血管通畅的希望。我有 一直致力于抑制 p38-MK2“应激反应”信号通路作为更全面的 IH 针对驱动病理性 VSMC 表型转换的潜在机制的治疗。在我最近的 研究表明，通过使用静电复合的新型肽治疗剂 (MK2i) 抑制 MK2 一种用于形成纳米复合物（MK2i-NP）的 pH 敏感内体溶解聚合物被证明在 抑制 VSMC 增殖、表型转换和 IH。在血管旁路移植术的背景下，一只兔子 血管移植模型表明，单次术中使用 MK2i-NP 进行治疗（局部外植 组织）在术后 28 天抑制新内膜形成，并减轻手术期间 VSMC 表型转换 移植后急性（7 天）应激反应阶段。我们假设体内基于导管的递送 MK2i 与球囊血管成形术相结合将防止 VSMC 表型转换并防止 再狭窄和血管衰竭。为了模拟专用导管的体内输送，我将开发一种离体 生物反应器系统并应用该系统评估压力对 MK2i 渗透和保留的影响 在血管壁中。此外，我们将使用生物反应器来评估药代动力学和药效学 离体动脉中的 MK2i。最后，根据初始工作中优化的压力条件，我们将应用 专门的闭塞灌注导管在血管腔内创建一个“腔室”，通过该腔室 MK2i-NP 可以可控地施用，以对流转移到体内血管壁中。该系统将 部署在猪模型中以评估体内 MK2i 递送对维持 VSMC 收缩的影响 PTA 后的表型和整体血管通畅性。