Targeted therapy to reverse aortic aneurysms

逆转主动脉瘤的靶向治疗

• 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
• 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

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.

项目摘要 主动脉瘤（AA）是以动脉壁扩张为特征的退行性疾病 微结构破坏AA是一种危及生命的疾病，可能导致夹层、破裂， 甚至是致命的。高血压、动脉粥样硬化和吸烟会增加AA发生和破裂的风险。 一些遗传性结缔组织疾病，如马凡氏综合征、Loeys-Dietz综合征或Ehlers-Danlos综合征， 增加AA的风险。由于手术风险，仅建议对大型动脉瘤进行手术干预 或者那些增长率高的国家。然而，一些小的动脉瘤破裂，而许多较大的动脉瘤从未破裂。 多达90%的检测到的AAA是小的，不符合手术标准;这些患者是“警惕”的。 “等待”，没有任何治疗。目前，没有药物方法可用于阻止AAA进展。 我们已经开发了一种新的纳米颗粒（NP）递送系统，其与独特的弹性蛋白抗体缀合， 仅针对降解的血管弹性蛋白，这是所有动脉瘤的标志，称为DESTINeD。我们已经发现 多酚-五没食子酰葡萄糖（PGG）在与以下物质一起递送时的弹性蛋白稳定和再生潜力 DESTINeD.我们假设通过稳定残余弹性蛋白来增加动脉瘤的强度 胶原蛋白和再生丢失的弹性蛋白将阻止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-β中和抗体或在饮用水中加入β氨基丙腈、BAPN） 测试使用DESTIENeD治疗是否可以预防破裂以及是否可以恢复动脉稳态 炎症减少。在具体目标2中，我们将检验降解弹性蛋白靶向PGG- 装载的纳米颗粒可以预防马凡氏综合征小鼠模型中的动脉瘤破裂。马凡氏综合征 是由导致结缔组织中弹性蛋白沉积功能障碍的β-淀粉样蛋白-1基因突变引起的， 并且这些患者中的许多发展为严重的心血管并发症，例如胸部AA。Fbn1R/R 纯合子小鼠出现普遍存在的主动脉弹性蛋白断裂，一种炎症-纤维增生反应， 以及炎症介导的弹性蛋白溶解，使得99%的人在2-6个月大时死于主动脉破裂。这里我们 我们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，修复ECM，防止血管平滑肌细胞增生。 破裂和死亡作为我们治疗的临床前证据，将使用腹部AA的猪模型， 具体目标3：测试DESTINeD纳米颗粒与人源化弹性蛋白抗体是否会阻止生长， 撤销现有的AA。如果成功，我们将成为第一个可以转化为预防主动脉粥样硬化的注射疗法。 扩张和破裂。