NCT04586452

NIH CCR2 AAA Study

CCR2 Targeted Molecular Imaging and Treatment of Abdominal Aortic Aneurysms

• Status: Completed
• Phase: EARLY_Phase 1
• Study type: Interventional
• Enrollment: 50 (actual)
• Sponsor: Washington University School of Medicine · Academic / Other
• Sex: All
• Age: 40 Years
• Healthy volunteers: Not accepted

Summary

Abdominal aortic aneurysm (AAA) is a degenerative vascular disease, which is typically asymptomatic until rupture, resulting in high mortality. AAAs are more prevalent in men over age 65, though rupture is disproportionately higher in women. Due to nonlinear and unpredictable aortic dilatation, it is challenging to predict the AAA rupture using clinical diagnostics based on morphology. No medical therapy is used clinically to treat AAA, and there is an unmet need for clinically translatable, molecular biomarkers of AAA disease activity for surveillance and patient-specific management. The goal of this proposal is to develop a new approach for the diagnosis and targeted therapy of AAA.

Detailed description

This project addresses the absence of a reliable diagnostic modality and medical therapy to prevent abdominal aortic aneurysm (AAA) growth and rupture in patients, leading to high mortality in those over the age of 65 years old. Due to the pathogenic role of the monocyte chemoattractant protein-1 / C-C chemokine receptor type 2 (MCP-1/CCR2) axis in AAA, we propose to study the ability of 64Cu-DOTA-ECL1i PET/CT to predict the murine AAA rupture and serve as a companion diagnostic to assess CCR2 molecular therapy of murine AAA. We will perform the first-in-patient evaluation of 64Cu-DOTA-ECL1i PET/CT to image and detect AAA inflammation in a preoperative setting and acquire key biological information from AAA specimens collected at the time of open AAA repair, in order to assess the potential of 64Cu-DOTA-ECL1i PET in the management of AAA patients. Preclinical and clinical research demonstrated that monocyte chemotactic protein-1/ chemokine (C-C motif) receptor 2 (MCP-1/CCR2) plays an important role in the pathogenesis of AAAs. This axis specifically promotes AAA formation and development by mediating the recruitment of circulating LY6Chigh monocytes and infiltration of macrophages, which leads to the degradation of elastic and collagen. In AAA mouse models, the genetic depletion or specific inhibition of CCR2 significantly decreased the production of matrix metalloproteinases (MMPs) and formation of aneurysms, suggesting the potential of CCR2 as a biomarker for AAA imaging and pre-screening for targeted intervention. We have developed a specific CCR2 binding radiotracer, 64Cu-DOTA-ECL1i, for targeted imaging of CCR2 positive pro-inflammatory monocytes/macrophages, in multiple animal inflammatory models using positron emission tomography (PET). This investigational PET tracer is being used under Exploratory IND 137620 for research imaging studies in human subjects. In patients with inflammatory diseases, 64Cu-DOTA-ECL1i PET revealed specific detection of CCR2+ cells in inflammatory tissues. In a rat AAA model, 64Cu-DOTA-ECL1i PET revealed specific localization within the aneurysm, as well as sensitive detection of CCR2+ inflammatory cells. Human AAA specimens demonstrated specific binding of 64Cu-DOTA-ECL1i to CCR2 by autoradiography. Thus, we hypothesize that 64Cu-DOTA-ECL1i detect CCR2+ cells mediated aneurysmal activity and can be utilized for AAA molecular imaging. We propose to assess the potential of 64Cu-DOTA-ECL1i as a biomarker for AAA patients imaging.

Conditions

• Abdominal Aortic Aneurysm (AAA)
• No Abdominal Aortic Aneurysm (Non-AAA)

Interventions

Type	Name	Description
DIAGNOSTIC_TEST	AAA Group (Aim 3A)	The primary goal is to relate preoperative 64Cu-DOTA-ECL1i AAA uptake with CCR2+ cell activity in AAA tissue collected at the time of open repair. We will image AAA patients pre-operatively and collect tissue at the time of open repair in an attempt to demonstrate ex-vivo tissue corroboration of our imaging findings (n=20, 10 women and 10 men). Participants with AAA will undergo routine clinical evaluation including ultrasound, CT scan and scheduling of open surgical repair. We will record age and tobacco use. If a renal function blood test has not been performed within the past 90 days, we will draw \~2 teaspoons of blood for a creatinine test. A contrast dye will be used for the CT portion of the PET-CT scan. Those having open surgery, their PET/CT imaging will be within 7-14 of the surgery and if available, collection of discarded aortic tissue at the time of surgery.
DIAGNOSTIC_TEST	Non-AAA Group	We will determine the retention of 64Cu-DOTA-ECL1i in abdominal aorta of non-AAA volunteers (n=10, 5 women and 5 men). This group of participants will have a documented absence of AAA by screening ultrasound that was previously obtained as part of standard care. Both men and women, above the age of 40, with or without active tobacco use will be considered for participation.
OTHER	Ex Vivo Human AAA Specimens (Aim 2A)	The primary objective of this sub-aim is to assess the sensitivity and specificity of 64Cu-DOTA-ECL1i binding to ex vivo to human AAA specimens from the Washington University Vascular Surgery Biobank (VS-BB). We will first perform a histopathological evaluation of human AAA specimens (n=75, including samples from this study) and categorize them based on clinical status (e.g, diameter) and degree of inflammation. We will consider healthy, nonatherosclerotic aorta (n=25) as negative controls, and non-aneurysmal aortas (n=25) from patients that have undergone surgery for aortoiliac occlusive disease as positive controls.
OTHER	Relationship between radiotracer and CCR2 (Aim 2B)	The objective of this sub-aim is to better understand the relationship between the levels of CCR2+ inflammatory cells and the inflammatory and clinical status of AAA, to gain insight into the importance of proinflammatory monocytes/macrophages in the development of AAA disease at the time of elective AAA repair. We will correlate the level of MMP expression and activity, as well as cytokine profiles, of each specimen, with the associated histopathological features. The relationship between 64Cu-DOTA-ECL1i binding and CCR2 expression in tissues with different degrees of disease severity will be evaluated using Pearson or Spearman correlation coefficients. This will allow us to speculate as to how tracer uptake will perform in vivo and what that uptake represents in regard to disease severity.
DIAGNOSTIC_TEST	AAA Group (Aim 3B-Reproducibility)	We will demonstrate consistent 64Cu-DOTAECL1i uptake by performing repeated imaging studies in a separate group of non-surgical AAA patients (n=20, 10 women and 10 men). Completion of this sub-aim will provide support for the use of 64Cu-DOTA-ECL1i PET for evaluating AAA disease in a reliable fashion. These participants will have another PET/CT imaging study performed 10-14 days after the first PET/CT in order to determine the ability to reproduce the uptake results of Cu-64-DOTA-ECL1i. The physician will assess the participant's willingness and eligibility to have a second PET/CT scan.

Timeline

• Start date: 2021-02-17
• Primary completion: 2022-04-04
• Completion: 2022-04-04
• First posted: 2020-10-14
• Last updated: 2025-07-15

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study