Targeted therapy to reverse aortic aneurysms

逆转主动脉瘤的靶向治疗

基本信息

批准号：
10659497
负责人：
Naren R Vyavahare
金额：
$ 68.17万
依托单位：
CLEMSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659497
关键词：
Abdomen Abdominal Aortic Aneurysm Adverse event Age Months Albumins Aneurysm Angiotensin II Animal Model Anti-Inflammatory Agents Antibodies Anxiety Aorta Aortic Aneurysm Aortic Rupture Apolipoprotein E Area Arteries Atherosclerosis Blood Vessels Cardiovascular system Cells Cessation of life Chest Clinical Collagen Collagen Fiber Connective Tissue Connective Tissue Diseases DNA Sequence Alteration Data Defect Degenerative Disorder Deposition Detection Deterioration Diagnosis Disease Dissection Ehlers-Danlos Syndrome Elastases Elastic Fiber Elasticity Elastin Elective Surgical Procedures Etiology Experimental Models Exposure to Extracellular Matrix Extracellular Matrix Degradation FBN1 Family suidae Female Funding Genes Genetic Genetic Diseases Glucose Growth Homeostasis Homozygote Human Human body Hypertension Infection Inflammation Inflammatory Inflammatory Infiltrate Infusion procedures Inherited Injectable Injections Intraperitoneal Injections Life Location Marfan Syndrome Matrix Metalloproteinases Medial Mediating Methods Modeling Modification Mus Mutation Names Natural regeneration Operative Surgical Procedures Pathologic Patient observation Patients Peptide Hydrolases Pharmaceutical Preparations Pharmacological Treatment Principal Investigator Progress Reports Protein-Lysine 6-Oxidase Publishing Pump Quality of life Rattus Recommendation Residual state Risk Risk Factors Rupture Ruptured Abdominal Aortic Aneurysm Ruptured Aneurysm Ruptured Aortic Aneurysms Smoking System Testing Thoracic Aortic Aneurysm Thoracic aorta Tissues Tobacco smoking behavior Transforming Growth Factor beta Translating Unnecessary Surgery Work abdominal aorta adverse outcome beta Aminopropionitrile calcification clinically relevant collagenase drinking water early onset heritable connective tissue disorder improved individual patient inflammatory marker male mortality mouse model nanoparticle nanoparticle delivery neutralizing antibody novel pharmacologic polyphenol porcine model pre-clinical prevent programs regeneration potential repaired response screening success targeted treatment therapeutic nanoparticles traumatic event

项目摘要

Project Summary Aortic aneurysms (AA) are degenerative diseases characterized by dilation caused by arterial wall microarchitecture destruction. AAs are a life-threatening condition with the potential to lead to dissection, rupture, and even fatality. High blood pressure, atherosclerosis, and smoking increase the risk of AA initiation and rupture. Some inherited connective tissue disorders, such as Marfan, Loeys-Dietz, or Ehlers-Danlos syndromes, can also increase the risk for AA. Due to procedural risks, surgical intervention is only recommended for large aneurysms or those with a high rate of growth. However, several small aneurysms rupture while many larger ones never do. As many as 90% of detected AAAs are small and do not meet the surgical criteria; these patients are “watchfully waiting” without any treatment. Currently, no pharmacological approaches are available to stop AAA progression. We have developed a novel nanoparticle (NP) delivery system conjugated with a unique elastin antibody that targets only degraded vascular elastin, a hallmark of all aneurysms, named DESTINeD. We have discovered elastin stabilizing and regeneration potential of polyphenol-pentagalloyl glucose (PGG) when delivered with DESTINeD. We hypothesize that increasing the strength of the aneurysmal aorta by stabilizing residual elastin and collagen and regenerating lost elastin will prevent the expansion and rupture of AAs. In Specific Aim 1, we will use an abdominal aortic rupture mouse models (Angiotensin II infusion with either intraperitoneal injection of TGF-b neutralizing antibody or adding β Aminopropionitrile, BAPN in drinking water) to test if rupture can be prevented using DESTIENeD therapy and whether arterial homeostasis will be restored and inflammation reduced. In Specific Aim 2, we will test the hypothesis that degraded elastin-targeting PGG- loaded nanoparticles can prevent aneurysm rupture in a mouse model of Marfan Syndrome. Marfan syndrome is caused by mutation of the fibrillin-1 gene that causes dysfunctional elastin deposition in connective tissues, and many of these patients develop severe cardiovascular complications such as thoracic AAs. Fbn1R/R homozygote mice develop ubiquitous aortic elastin fragmentation, an inflammatory-fibroproliferative response, and inflammation-mediated elastolysis so that 99% die of aortic rupture between 2-6 months of age. Here we will test if our nanoparticle therapy can stabilize elastin and collagen and repair ECM and prevent aneurysmal rupture and death. As a preclinical proof for our therapy, a swine model of the abdominal AA will be used in Specific Aim 3 to test if DESTINeD nanoparticles, with a humanized elastin antibody, would arrest growth and reverse existing AAs. If successful, ours will be the first injectable therapy that can be translated to prevent aortic dilation and rupture.

项目概要主动脉瘤（AA）是一种退行性疾病，其特征是动脉壁引起的扩张微结构破坏是一种危及生命的疾病，有可能导致解剖、破裂、高血压、动脉粥样硬化和吸烟都会增加 AA 发生和破裂的风险。一些遗传性结缔组织疾病，如马凡综合征、洛伊斯-迪茨综合征或埃勒斯-当洛斯综合征，也可能导致由于手术风险，仅建议对大动脉瘤进行手术干预。然而，一些小动脉瘤会破裂，而许多较大的动脉瘤却永远不会破裂。多达 90% 的检测到的 AAA 都很小，不符合手术标准，这些患者需要“警惕”。目前，尚无药物方法可用于阻止 AAA 进展。我们开发了一种新型纳米颗粒 (NP) 递送系统，与独特的弹性蛋白抗体结合，我们发现，仅针对降解的血管弹性蛋白，这是所有动脉瘤的标志，名为 DESTINeD。多酚五没食子酰葡萄糖 (PGG) 的弹性蛋白稳定和再生潜力我们攀登了这个目标，通过稳定残余弹性蛋白来增加动脉瘤主动脉的强度。胶原蛋白和再生失去的弹性蛋白将防止 AA 的扩张和破裂。在具体目标 1 中，我们将使用腹主动脉破裂小鼠模型（血管紧张素 II 输注腹腔注射TGF-b中和抗体或在饮用水中添加β氨基丙腈、BAPN）测试是否可以使用 DESTIENeD 疗法来预防破裂以及动脉稳态是否会恢复在具体目标 2 中，我们将测试降解弹性蛋白靶向 PGG- 的假设。负载纳米颗粒可以防止马凡氏综合症小鼠模型的动脉瘤破裂。由 fibrillin-1 基因突变引起，导致结缔组织弹性蛋白沉积功能失调，其中许多患者出现严重的心血管并发症，例如胸部 AA。纯合子小鼠会出现普遍存在的主动脉弹性蛋白碎片，这是一种炎症纤维增殖反应，和炎症介导的弹性组织溶解，导致 99% 的人在 2-6 个月大时死于主动脉破裂。将测试我们的纳米颗粒疗法是否可以稳定弹性蛋白和胶原蛋白并修复 ECM 并预防动脉瘤作为我们治疗的临床前证据，将使用猪腹部 AA 模型。具体目标 3 测试带有人源化弹性蛋白抗体的 DESTINeD 纳米颗粒是否会阻止生长并如果成功的话，我们的方法将逆转现有的 AA，这将是第一个可用于预防主动脉瘤的注射疗法。扩张和破裂。