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。

基本信息

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
项目类别：
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

项目摘要

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疾病， PAD 影响了美国超过 650 万人，导致血液流动减少，导致肢体疼痛、伤口无法愈合，在极端情况下，甚至死亡的经皮腔内血管成形术（PTA），涉及球囊充气。在阻塞部位重新打开动脉管腔，是 PAD 的常见治疗方法，但血管壁应力较大。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，动脉重新变窄。大多数经过 PTA 治疗的血管在最初 12 个月内就会衰竭。再狭窄是由内膜病理过程引起的。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）和炎症细胞因子的合成活动产生新内膜，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。减少 IH 的策略仅侧重于通过使用药物涂层球囊来抑制 VSMC 增殖，然而，在我的临床试验中，这些方法并没有显示出改善血管通畅的希望。一直致力于抑制 p38-MK2“应激反应”信号通路作为更全面的 IH 在我最近的研究中，针对驱动病理性 VSMC 表型转换的潜在机制的治疗。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 pH 敏感的内体聚合物形成纳米复合物 (MK2i-NPs) 被证明在在血管旁路移植术中抑制 VSMC 增殖、表型转换和 IH。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 表型转换我们捕捉到了移植后的急性（7 天）应激反应阶段，基于导管的递送。 MK2i 与球囊血管成形术相结合将防止 VSMC 表型转换并防止为了模拟特殊导管的体内输送，我将开发一种离体导管。生物反应器系统并应用该系统评估压力对 MK2i 渗透和保留的影响此外，我们将使用生物反应器来评估药代动力学和药效学。最后，基于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-NPs 可以可控地施用到体内血管壁中。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。