Document text
Principal Investigator: CHARLES GINSBERG
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $635,333
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Adverse Experience><Adverse event><Albuminuria><Atomic Medicine><Binding><Biodistribution><Biological Markers><Bladder><Bladder Urinary System><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Serum><Cell Function><Cell Physiology><Cell Process><Cell surface><Cellular Function><Cellular Physiology><Cellular Process><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Clinical Evaluation><Clinical Testing><Clinical Trials><Clinical Trials Design><Common Rat Strains><Creatinine><Data><Development><Diabetes Mellitus><Diabetic Kidney Disease><Diabetic Nephropathy><Diabetic mouse><Diagnosis><Diagnostic><Diagnostic tests><Discipline of Nuclear Medicine><Disease><Disorder><Dose><Drug Kinetics><ERPF><Early Diagnosis><Early treatment><Early-Stage Clinical Trials><Effective Renal Plasma Flow><European><Evaluation><Future><Glomerular Filtration Rate><Glomerular Mesangial Cell><Half-Life><Heart><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Histologic><Histologically><Human><Hypertension><Hypertensive Nephropathy><Image><Individual><International><Intervention Trial><Interventional trial><Intravenous><Journals><Kidney><Kidney Diseases><Kidney Urinary System><Kinetics><Laboratories><Laboratory Study><Liver><Liver Cells><Macrophage><Magazine><Modern Man><Molecular><Molecular Interaction><Motivation><Mφ><Nephropathy><Nuclear Medicine><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathology><Patients><Periodicals><Persons><Pharmacokinetics><Phase 1 Clinical Trials><Phase I Clinical Trials><Plasma><Plasma Serum><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Prevalence><Protocol><Protocols documentation><Publishing><Rad.-PET><Radiolabeled><Radiology / Radiation Biology / Nuclear Medicine><Radiopharmaceutical Compound><Radiopharmaceuticals><Rat><Rats Mammals><Rattus><Renal Disease><Renal Hypertension><Reticuloendothelial System, Serum, Plasma><Risk><SPECT><SPECT imaging><Safety><Sampling><Scanning><Serum><Single-Photon Emission-Computed Radionuclide Tomography><Specificity><Subcellular Process><Surface><Tc 99m><Technetium 99m><Testing><Therapeutic Intervention><Time><Urine><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><bio-markers><biologic marker><biomarker><chemical safety><chronic kidney disease><clinical test><clinical trial protocol><db/db mouse><design><designing><developmental><diabetes><diabetes mouse model><diabetic><diabetic patient><disease model><disorder model><drug development><early detection><early therapy><first in man><first-in-human><glomerular filtration><hepatic body system><hepatic organ system><high blood pressure><high risk><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><hypertensive kidney><imaging><imaging agent><imaging biomarker><imaging marker><imaging-based biological marker><imaging-based biomarker><imaging-based marker><intervention therapy><kidney cortex><kidney cortical portion><kidney disorder><kidney imaging><kidney medulla><kidney medullary portion><mesangial cell><micro PET><micro positron emission tomography><microPET><molecular imaging><molecule imaging><nuclear imaging><open label><open label study><periodic><periodical><phase 1 trial><phase I protocol><phase I trial><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><radiation absorbed dose><radioactive drugs><radiolabeling><radiologically labeled><radiotherapeutic drugs><renal><renal cortex><renal disorder><renal medulla><research clinical testing><safety assessment><single photon emission computed tomography><standard of care><tool><urinary bladder>