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:10375348
- 负责人:
- 金额:$ 62.7万
- 依托单位:
- 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:
- 关键词:Adverse eventAlbuminuriaBindingBiodistributionBiological MarkersBladderBloodCell physiologyCell surfaceChemicalsChronic Kidney FailureClinicalClinical TrialsClinical Trials DesignClinical trial protocol documentCreatinineDataDevelopmentDiabetes MellitusDiabetic NephropathyDiabetic mouseDiagnosisDiagnosticDiagnostic testsDiscipline of Nuclear MedicineDiseaseDisease modelDoseDrug KineticsEarly DiagnosisEarly treatmentEffective Renal Plasma FlowEuropeanEvaluationFutureGlomerular Filtration RateGlomerular Mesangial CellHalf-LifeHeartHepatocyteHistologicHumanHypertensionImageIndividualInternationalIntervention TrialIntravenousJournalsKidneyKidney DiseasesKineticsLaboratoriesLaboratory StudyLiverMolecularMotivationPathologyPatientsPeriodicityPersonsPhase I Clinical TrialsPlasmaPositron-Emission TomographyPrevalenceProtocols documentationPublishingRadiolabeledRadiopharmaceuticalsRattusRenal HypertensionRiskSafetySamplingScanningSerumSpecificitySurfaceTechnetium 99mTestingTherapeutic InterventionTimeUrinebasedb/db mousedesigndiabeticdiabetic patientdrug developmentfirst-in-humanglomerular filtrationhigh riskimaging agentimaging biomarkerkidney cortexkidney imagingkidney medullamacrophagemesangial cellmicroPETmolecular imagingnuclear imagingopen labelphase I trialradiation absorbed doseresearch clinical testingsingle photon emission computed tomographystandard of caretool
项目摘要
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 & G5, 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.
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。约 40% 的人患有糖尿病
发展为糖尿病肾病(DN)。其中百分之二十的人没有遵循典型的道路
慢性肾脏病是白蛋白尿和血清肌酐数十年来缓慢增加的疾病,目前
慢性肾脏病(KD)监测的护理标准。因此,存在未满足的临床需求
用于慢性川崎病最初十年的常规监测。
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敏感,有效肾
血浆流量或白蛋白尿,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。这
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 Tc- 两个剂量水平(2.0 和 20 nmol)的生物分布
99m-替马诺西普。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
扩张; G2,轻度MCM扩张; G3&G5,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。
项目成果
期刊论文数量(0)
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CHARLES GINSBERG其他文献
CHARLES GINSBERG的其他文献
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{{ truncateString('CHARLES GINSBERG', 18)}}的其他基金
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 - 财政年份:2021
- 资助金额:
$ 62.7万 - 项目类别:
Influence of Vitamin D Binding Protein on Clinical Measures of Vitamin D Status and Bone Health
维生素 D 结合蛋白对维生素 D 状态和骨骼健康临床指标的影响
- 批准号:
10394279 - 财政年份:2018
- 资助金额:
$ 62.7万 - 项目类别:
Influence of Vitamin D Binding Protein on Clinical Measures of Vitamin D Status and Bone Health
维生素 D 结合蛋白对维生素 D 状态和骨骼健康临床指标的影响
- 批准号:
9910387 - 财政年份:2018
- 资助金额:
$ 62.7万 - 项目类别:
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