Renal Molecular Imaging of Mesangial Cell Function with Tc-99m-Tilmanocept

使用 Tc-99m-Tilmanocept 对系膜细胞功能进行肾脏分子成像

• 批准号: 10733137
• 负责人: CHARLES GINSBERG
• 金额: $ 10.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733137
• 关键词: Albuminuria; Binding; Biodistribution; Biological Markers; Bladder; Blood; Cell physiology; Cell surface; Chronic Kidney Failure; Clinical; Creatinine; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diagnostic; Diagnostic tests; Disease; Disease Marker; Disease Progression; Disease model; Dose; Early Diagnosis; Early treatment; Effective Renal Plasma Flow; Future; Glomerular Filtration Rate; Goals; Half-Life; Health; Heart; Hepatocyte; Histologic; Human; Hypertension; Image; Imaging Techniques; Impairment; Individual; Injury; Injury to Kidney; International; Kidney; Kidney Diseases; Liver; Macrophage; Measures; Molecular; Outcome; Pathogenesis; Pathogenicity; Pathology; Patient Outcomes Assessments; Patients; Periodicals; Persons; Phase I Clinical Trials; Plasma; Play; Prevalence; Process; Prognosis; Rattus; Renal Hypertension; Renal Tissue; Renal function; Risk Assessment; Role; Sampling; Serum; Severity of illness; Structure; Technetium 99m; Therapeutic Intervention; Tissues; Tubular formation; Urine; biomarker validation; clinical predictors; clinically significant; db/db mouse; diabetic; diabetic patient; glomerular filtration; glomerular function; high risk; imaging agent; imaging biomarker; improved; kidney cortex; kidney imaging; kidney medulla; macroalbuminuria; mesangial cell; microPET; molecular imaging; novel marker; open label; parent grant; prevent; prognostication; progression risk; single photon emission computed tomography; standard of care; tissue injury; tool

Parent Grant Summary In 2017 the International Diabetes Federation estimated that the worldwide prevalence of diabetes would increase from 415 million in 2015 to 642 million in 2040. Approximately 40% of individuals with diabetes develop diabetic nephropathy (DN). Twenty percent of these individuals do not follow the typical path toward chronic kidney disease, which is a slow multi-decade increase in albuminuria and serum creatinine, the current standard- of-care for surveillance of chronic kidney disease (KD). Consequently, there is an unmet clinical need for routine surveillance during the first decade of chronic KD. We propose external imaging of mesangial cell function as a biomarker for diabetic nephropathy. Our reasoning is based on the following. Mesangial cell matrix (MCM) expansion is a histologic hallmark of diabetic nephropathy, which precedes the reduction of a patient's glomerular filtration rate or increase in albuminuria. Additionally, all the clinical manifestations of diabetic nephropathy are highly correlated with MCM expansion. There currently does not exist an imaging, serum, or urine biomarker that is sensitive to mesangial cell function. Current imaging agents and biomarkers are only sensitive to glomerular filtration, effective renal plasma flow, or albuminuria, which are altered late in the disease when therapeutic intervention is not effective. We propose a Phase 1 clinical trial of Tc-99m-tilmanocept, which accumulates in the liver and kidneys. The molecular mechanism is binding to CD206, which resides on the cell surface of fixed macrophages within the liver and mesangial cells within the kidney. We present preliminary data consisting of human SPECT/CT and rat microPET images of renal cortex. Additionally, we present evidence of sensitivity to MCM expansion via Tc- 99m-tilmanocept dynamic imaging of db/db mice, an accepted disease model of diabetic nephropathy. We propose an open-label study to investigate the biodistribution at two dose levels (2.0 & 20 nmol) of Tc-99m-tilmanocept. We will study 5 groups at each dose (10 subjects each): 1) Advance DN, 2) early DN, 3) diabetes with no kidney disease, 4) advanced hypertension (HTN) with KD, and 5) HTN without KD. The study will include a 30-min dynamic followed be a 30-min kidney SPECT/CT, and periodic blood and urine sampling. Dynamic imaging will yield plasma clearance half-lifes, and liver and kidney accumulation rates; SPECT/CT will yield SUVs for the heart, liver, renal cortex, renal medulla. We will also calculate urinary bladder accumulation. We expect the renograms and biodistribution data to reflect the following pathology: Group 1, severe MCM expansion; G2, mild MCM expansion; G3 & GS, no MCM expansion; and G4, low MCM expansion. This study is the necessary first step toward FDA-approval of Tc-99m-tilmancoept as a kidney imaging agent. The study will also provide evidence of imaging sensitivity to MCM expansion in DN patients, and insensitivity to patients with HTN. This senerio will be required if Tc-99m-tilmanocept renograms as "first-line" diagnostic test for diabetic patients.

家长赠款摘要 2017年，国际糖尿病联合会估计，糖尿病的全球患病率将 从2015年的4.15亿增加到2040年的6.42亿。大约40％的糖尿病患者发展 糖尿病性肾病（DN）。这些人中有20％不遵循通往慢性的典型路径 肾脏疾病，这是蛋白尿和血清肌酐的慢速增加，这是当前的标准 - 慢性肾脏疾病（KD）监测的护理。因此，有未满足的临床需要 慢性KD的前十年监视。 我们提出了对糖尿病性肾病的生物标志物的外部成像。我们的 推理基于以下内容。肾小球细胞基质（MCM）扩展是糖尿病的组织学标志 肾病是在降低患者肾小球滤过率或蛋白尿增加之前的肾病。 此外，糖尿病性肾病的所有临床表现都与MCM扩张高度相关。 当前不存在对膜细胞敏感的成像，血清或尿液生物标志物 功能。当前的成像剂和生物标志物仅对肾小球过滤敏感 当治疗干预无效时，流量或蛋白尿在疾病后期会改变。 我们提出了TC-99M-Tilmanocept的1期临床试验，该试验积累在肝脏和肾脏中。 分子机制与CD206结合，该机制位于固定巨噬细胞的细胞表面上 肾脏内的肝脏和肾小球细胞。我们提供了由人类SPECT/CT和 肾皮质的大鼠微型图像。此外，我们提供了通过TC-敏感性敏感性的证据 DB/DB小鼠的99m-Tilmanocept动态​​成像，这是一种糖尿病肾病的可接受疾病模型。 我们提出了一项开放标签研究，以调查两个剂量水平（2.0＆20 nmol）的生物分布 TC-99M-Tilmanocept。我们将在每个剂量上研究5组（每个受试者10个）：1）Advance DN，2）早期DN，3） 没有肾脏疾病的糖尿病，4）具有KD的晚期高血压（HTN），而没有KD的HTN。研究 将包括30分钟的动态，然后是30分钟的肾脏SPECT/CT，以及定期的血液和尿液采样。 动态成像将产生血浆清除率的一半，以及肝脏和肾脏积累率； SPECT/CT会 产生心脏，肝脏，肾皮质，肾髓质的SUV。我们还将计算膀胱积聚。 我们希望肾脏图和生物分布数据将反映以下病理：第1组，严重 MCM扩展； G2，轻度MCM扩展； G3＆GS，没有MCM扩展；和G4，低MCM扩展。 这项研究是FDA批准TC-99M-TILMANCOEPT作为肾脏成像的必要第一步 代理人。该研究还将提供对DN患者MCM扩展敏感性成像的证据，以及 对HTN患者不敏感。如果TC-99M-Tilmanocept肾脏图作为“第一线”，则需要此Senerio 糖尿病患者的诊断测试。