NIH CCR2 AAA Study
NIH CCR2 AAA Study
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.
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.
Inclusion Criteria:

 -  Ages 40 - 80 years old

 -  With or without active tobacco use

 -  Medically managed hypertension and hyperlipidemia

 -  Asymptomatic patients with known AAAs by CT angiogram (men ≥ 5.5 cm, women ≥ 5.0cm).

 -  Non-AAA volunteers will have a documented absence of AAA by exam and recent screening
 ultrasound (US).

 -  Able to comprehend and willing to follow instructions for the study procedures as
 called for by the protocol

 -  No history of claustrophobia or other preventing condition that has previously or
 would interfere with completion of protocol specified imaging sessions

 Exclusion Criteria:

 -  Inability to receive and sign informed consent.

 -  Patients with Stage ≥ 4 chronic renal failure (calculated by modification of diet in
 renal disease eGFR equation [to minimize confounding imaging variables])

 -  Documented allergy to iodinated contrast and/or shellfish.

 -  Patients with an unstable clinical condition that in the opinion of the principal
 investigators or designee precludes participation in the study.

 -  Inability to tolerate 60 minutes in a supine position with arms down at sides, as
 necessary for PET/CT.

 -  Positive pregnancy test or lactating.

 -  Other conditions such as symptomatic/recently treated coronary disease, cancer
 requiring oncologic management, or autoimmune/inflammatory diseases (e.g., rheumatoid
 arthritis or multiple sclerosis) that are known to have increased associated CCR2
 expression.

 -  Non-AAA volunteers may not carry a diagnosis of aortoiliac occlusive disease, as
 documented by their treating vascular surgeon, as significantly progressed
 atherosclerotic disease may demonstrate exaggerated, associated CCR2 expression.