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

基本信息

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
项目类别：
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

项目摘要

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.

家长资助摘要 2017年，国际糖尿病联合会估计，全球糖尿病患病率将糖尿病患者将从 2015 年的 4.15 亿增加到 2040 年的 6.42 亿。大约 40% 的糖尿病患者患有糖尿病糖尿病肾病（DN）。其中百分之二十的人没有遵循典型的慢性病路径肾脏疾病，白蛋白尿和血清肌酐在数十年中缓慢增加，目前的标准用于监测慢性肾病 (KD) 的非护理。因此，常规的临床需求尚未得到满足。慢性 KD 的第一个十年的监测。我们建议将系膜细胞功能的外部成像作为糖尿病肾病的生物标志物。我们的推理基于以下内容。系膜细胞基质（MCM）扩张是糖尿病的组织学标志肾病，先于患者肾小球滤过率降低或白蛋白尿增加。此外，糖尿病肾病的所有临床表现均与MCM扩张高度相关。目前不存在对系膜细胞敏感的成像、血清或尿液生物标志物功能。目前的显像剂和生物标志物仅对肾小球滤过、有效肾血浆敏感血流或白蛋白尿，在疾病晚期当治疗干预无效时发生改变。我们建议对 Tc-99m-tilmanocept 进行 1 期临床试验，该药物在肝脏和肾脏中积累。分子机制是与 CD206 结合，CD206 位于固定巨噬细胞的细胞表面肝脏和肾脏内的系膜细胞。我们提供的初步数据包括人类 SPECT/CT 和大鼠肾皮质的 microPET 图像。此外，我们还提供了通过 Tc- 对 MCM 扩展敏感的证据 db/db 小鼠的 99m-tilmanocept 动态成像，这是一种公认的糖尿病肾病疾病模型。我们提出了一项开放标签研究来调查两种剂量水平（2.0 和 20 nmol）的生物分布 Tc-99m-tilmanocept。我们将在每个剂量下研究 5 组（每组 10 名受试者）：1) 晚期 DN，2) 早期 DN，3) 无肾脏疾病的糖尿病，4) 伴有 KD 的晚期高血压 (HTN)，以及 5) 不伴有 KD 的高血压。研究将包括 30 分钟动态检查、随后 30 分钟肾脏 SPECT/CT 检查以及定期血液和尿液采样。动态成像将得出血浆清除半衰期以及肝脏和肾脏蓄积率； SPECT/CT 将产生心脏、肝脏、肾皮质、肾髓质的 SUV。我们还将计算膀胱蓄积量。我们期望肾图和生物分布数据反映以下病理：第 1 组，严重 MCM 扩展； G2，轻度MCM扩张； G3 & GS，无MCM扩展； G4，低MCM扩展。这项研究是 FDA 批准 Tc-99m-tilmancoept 作为肾脏成像药物的必要的第一步代理人。该研究还将提供 DN 患者中 MCM 扩张的影像学敏感性证据，以及对高血压患者不敏感。如果 Tc-99m-tilmanocept 肾图作为“一线”，则需要此高级糖尿病患者的诊断测试。