Novel Therapy for Diabetic PAD Monitored With Dual Isotope Multimodality Imaging

通过双同位素多模态成像监测糖尿病 PAD 的新疗法

• 批准号: 9003474
• 负责人: LYNNE L. JOHNSON
• 金额: $ 46.81万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9003474
• 关键词: Acute; Advanced Glycosylation End Products; Age; Amputation; Anatomy; Angiography; Animal Model; Animals; Antibodies; Applications Grants; Binding; Blocking Antibodies; Blood Vessels; Blood flow; Breeding; Catheters; Cell Culture Techniques; Cessation of life; Clinical Trials; Contralateral; Defect; Development; Diabetes Mellitus; Diabetic mouse; Dose; Family suidae; Glucose; Growth; Healed; Hindlimb; Hybrids; Hypoxia; Image; Immunoglobulin G; Implant; Individual; Infusion Pumps; Ischemia; Isolated limb perfusion; Isotopes; KDR gene; Knock-out; Lead; Left; Leg Ulcer; Ligation; Limb structure; Measurement; Measures; Miniature Swine; Modeling; Monitor; Mus; Muscle; Operative Surgical Procedures; Oxygen; Pathway interactions; Perfusion; Peripheral arterial disease; Pharmacotherapy; Placebos; Play; Property; Proteins; Pump; Radioisotopes; Recovery; Reporting; Risk; Role; Saline; Skeletal Muscle; Smooth Muscle Myocytes; Techniques; Thallium; Therapeutic Agents; Therapeutic Effect; Therapeutic Trials; Time; Tissues; Tracer; Treatment Efficacy; Vascular Diseases; Vascular Smooth Muscle; Weight; Work; X-Ray Computed Tomography; angiogenesis; artery occlusion; base; diabetic; disorder control; femoral artery; healing; improved; molecular imaging; multimodality; muscle form; non-diabetic; novel; novel therapeutics; osmotic minipump; public health relevance; receptor; receptor expression; receptor for advanced glycation endproducts; research study; response; restoration; single photon emission computed tomography; treatment response; treatment trial; uptake

 DESCRIPTION (provided by applicant): Symptomatic peripheral arterial disease (PAD) is a disabling condition in diabetes that can lead to leg ulcers, amputation, and death. There are currently no effective drug therapies for symptomatic PAD leaving surgical revascularization and interventional catheter based approaches and these can fail leading to limb loss. Developing novel therapies to treat PAD and to image response to therapy represents an unmet need. Advanced Glycation End products (AGEs) are produced by the nonenzymatic binding of glucose to proteins. AGEs bind a receptor (RAGE) to initiate pathways that play important roles in accelerating the development and progression of vascular disease in diabetes and by inhibiting the angiogenic response to limb ischemia. We developed a monoclonal anti-RAGE antibody for imaging and have shown in diabetic and hyperlipidemic mice and pigs that RAGE is expressed diffusely in vascular tissue of hindlimbs. We have also used imaging to confirm that knocking out RAGE restores the normal response to tissue hypoxia imposed by femoral artery ligation. We hypothesized that if our antibody is a blocking antibody it may have potential as a therapeutic agent for PAD and consequently performed confirmatory experiments in cell culture of vascular smooth muscle cells to document blocking properties. Using imaging confirmed by immunohistology we showed in diabetic mice with femoral artery ligation pretreated with antibody vs. saline greater angiogenesis at 5 days and improved blood flow at 24 days in the ischemic hind limb of antibody treated mice compared to placebo treated mice. In this grant application we propose a large animal treatment trial using dual isotope multimodality imaging to document response to therapy. Purpose bred diabetic Yucatan minipigs will receive either antibody or non-immune IgG for 2 months. After one month, catheter based unilateral femoral artery occlusion (FAO) will be performed in these pigs plus additional age matched and weight matched non-diabetic Yucatan minipigs. At 24 h (acute insult) and 28 days (healing) after FAO 201Tl hybrid SPECT/CT imaging will be performed for limb skeletal muscle perfusion and CT angiography for large vessel anatomy. At day 7 after FAO hybrid SPECT/CT imaging will be performed with 99mTc scVEGF-PEG-DOTA (scV/Tc) a novel probe that targets VEGF receptors 1 and 2 and shown in preliminary experiments in mice to track angiogenesis in limb ischemia. Regional hindlimb muscle perfusion will be quantified from uptake of thallium-201 for early and late time points and regional limb angiogenesis from uptake of scV/Tc probe for day 7. We expect that the reduction in perfusion defects from day 1 to 28 will be greater in the antibody treated compared to placebo treated pigs and the magnitude of this change will relate to the quantitative uptake of scV/Tc at day 7 and to the collateral vessel score at day 28. The result of the proposed work has the potential to serve as justification for further development of the antibody and this dual isotope multimodality imaging approach towards a clinical trial.

 描述（由适用提供）：症状性周围动脉疾病（PAD）是糖尿病中的残疾病，可导致腿部溃疡，截肢和死亡。目前，尚无有效的有症状垫的药物疗法，使手术血运重建和基于介入​​的导管方法可能导致肢体流失。开发用于治疗垫和对治疗反应的新型疗法代表了未满足的需求。晚期糖基化末端产物（年龄）是由葡萄糖与蛋白质的非酶结合产生的。年龄结合受体（RAGE），以引发在加速中起重要作用的途径，糖尿病中血管疾病的发展和进展，并抑制对肢体缺血的血管生成反应。我们开发了一种用于成像的单克隆抗升高抗体，并在糖尿病和高脂血症小鼠和猪中显示了愤怒在后肢的血管组织中散布。我们还使用成像来确认爆发愤怒会恢复股动脉连接施加的组织缺氧的正常反应。我们假设，如果我们的抗体是一种阻断抗体，它可能具有用于垫的治疗剂的潜力，因此在血管平滑肌细胞的细胞培养物中进行了确认实验，以记录阻断特性。使用免疫组织学证实的成像，我们在糖尿病小鼠中表明，与抗体和盐水在5天时的血管生成预处理的股动脉连接更大，与安慰剂处理小鼠相比，在缺血性抗体治疗的小鼠的缺血性后肢中，血管生成更大，并在24天的血流量改善。在此赠款应用中，我们提出了一项使用双同位素多模式成像的大型动物治疗试验，以记录对治疗的反应。目的繁殖糖尿病性丝兰少女将接受2个月的抗体或非免疫IgG。一个月后，将在这些猪中进行基于导管的单侧股动脉闭塞（FAO），再加上额外的年龄匹配和体重匹配的非糖尿病性尤卡坦小型米皮。 FAO 201TL混合SPECT/CT成像后24小时（急性侮辱）和28天（愈合）将用于肢体骨骼肌肉灌注和CT血管造影，以进行大容器解剖结构。在第7天，在FAO Hybrid Spect/CT成像后将使用99MTC SCVEGF-PEG-DOTA（SCV/TC）进行靶向VEGF受体1和2的新型探针，并在小鼠的初步实验中显示，以跟踪LIMB局部缺血中的血管生成。区域后肢的肌肉灌注将从2010年thallium-201对于早期和晚期的吸收以及第7天的SCV/TC探测的吸收中的肢体血管生成以及区域性肢体血管生成来量化。我们预计，与该抗体相比，在抗体中，从第1天开始减少了第1天的灌注到28的较高量，而抗体治疗的量很大，而量化量则是量化量的量子和量的量。以及第28天的附带船舶得分。拟议工作的结果有可能作为进一步开发抗体的理由，而这种双重同位素多模式成像方法用于临床试验。