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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

基本信息

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
项目类别：
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

项目摘要

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.