Imaging of Unstable Atherosclerotic Plaque via a Novel Magnetic Resonance (MR) Contrast Agent

The Problem

Heart attack (acute myocardial infarction) is predominantly caused by plaque in blood vessels rupturing or eroding.  Biological processes found to be associated with plaque progression and destabilization are inflammation, outward vessel wall remodelling and dysfunctional matrix synthesis and degradation.  The majority of plaques causing a heart attack do not cause a significant stenosis and are defined by their composition and biological activity.  Thus, detection of vulnerable plaques with X-ray or computed tomography (CT) has shown little success.

The Solution

Tropoelastin, a biological protein associated with vascular remodelling and the development of an unstable plaque, is up-regulated in ruptured plaque and has emerged as key biomarker to identify patients that are at risk of a heart attack.  A binding imaging agent has been created which is designed to target tropoelastin, consisting of a peptide binding sequence coupled to a MR “reporter” molecule that allows the agent to be detected by MRI.  By co-localising a MR coronary angiogram with the tissue biomarker, the imaging agent provides an imageable signal that will allow the clinician to identify the location and extent of a patient’s vulnerable plaques.

Benefits

The MR image provides combined biological and anatomical information about the underlying pathology of vulnerable plaques allowing the clinician to identify the location and extent of plaques carried by the patient.  The imaging agent will aid the detection of rupture-prone and heavily inflamed atherosclerotic plaques, and determine the prevalence of such plaques in patients with suspected heart disease, providing improved patient stratification and enabling more specific treatment regimens to be designed depending on the risk profile determined from the data.

At a public health level, screening using this new test could help reduce the number of heart attacks and the associated health care costs, maintain quality of life of such individuals and thus enable greater contribution to society via their continued economic contribution.

Figure 1.  Tropoelastin staining of rabbit aortic tissue allows differentiation between normal wall, stable and vulnerable (defined as ruptured plaque with intraluminal thrombus) plaque.

Applications

The technology could be used to monitor treatment response and to assess a patient’s disease status at a personalised level.  The underpinning biology also suggests great potential of this technology to be used to aid in the detection of aortic aneurysms and myocardial, liver and renal fibrosis.

Specifically, the product could be used to address the following indications:

1. Detection of vulnerable plaque in asymptomatic patients (primary prevention).  The clinical value here will lie in screening populations of at-risk patients, such as those with high blood pressure, high LDL cholesterol and smoking, and identifying symptom-free people at high risk of a cardiovascular event.
2. Detection of vulnerable plaques in patients (secondary prevention).  The clinical value will be derived from a greater insight into the most appropriate cardiovascular intervention (e.g., additional stents, more aggressive therapy) in patients diagnosed with coronary artery disease and/or who have already experienced a cardiac event; the technology will enable this via detection of vulnerable plaques, enabling greater insight into the patient’s disease status at an individual level and enabling monitoring of that pathophysiology.
3. The technology could also be used to monitor treatment responses to current and new therapeutic interventions.

In scenarios (1) and (2), the imaging test will strongly influence therapy choice and therapy monitoring (thus enabling stratified medicine), whilst re-assuring those obtaining moderate to low “scores” (via the diagnostic test), that their current level of intervention is correct.

IP Status

A patent application was filed with a priority date of 08 FEB 2011 and the subsequent international PCT application (published as WO 2012/107725) has been continued as national filings in China (CN 201280016618.6), Europe (EP 12706879.9), India (IN 1529/MUMNP/2013), Japan (JP 2013-553019) and USA (US 13/984,522).  Pre-clinical data is also available for licensing.

Commercial development partners are sought for the technology.  Exclusivity is available if required.