Detection and Therapy of Vulnerable Plaque with Photodynamic Compounds

Intellectual Property

ID:		1985
IP Type:		Licensable Technology
Title:		Detection and Therapy of Vulnerable Plaque with Photodynamic Compounds
Inventor:		Anderson, Richard Rox; Daghighian, Farhad; Elmaleh, David R.; Fischman, Alan; Gewirtz, Henry; Hamblin, Michael R.; Hasan, Tayyaba; Muller, James E.; Tawakol, Ahmed A
Summary:		Background: In the U.S. alone, roughly 2600 people die each day as a result of cardiovascular disease. Of the 1.5 million people each year who will suffer from a heart attack, 50-60% of these people had no documented history of cardiovascular disease. Acute coronary syndrome is a subset of serious sudden-onset cardiovascular diseases, including unstable angina, acute myocardial infarction and sudden cardiac death, that are caused by erosion or rupture of a specific kind of active atheromatous plaque known as ''vulnerable plaque.'' In contrast to the vast majority of plaque lesions which remain relatively stable and slowly occlude the vasculature, vulnerable plaques have higher frequency of rupture and are the leading causative agent of heart attacks, strokes, and cases of sudden death, recently estimated to be as high as 80-85%. These types of plaques are structurally and functionally distinguishable from stable atherosclerotic plaques and are almost impossible to easily distinguish from quiescent or stable atherosclerotic plaques using current imaging modalities which do not give sensitive information on plaque components and cap thicknesses (i.e. MRI, CT, myocardial perfusion imaging, angiography, intravascular ultrasound, thermography, OCT, reflectance, spectrospcopy). Post-mortem evidence suggests that vulnerable plaque rupture occurs most frequently in areas of the coronary arteries that are less than 50% stenosed. Current therapies to ameliorate the occlusive effects of atherosclerotic plaques, such as bypass surgery and angioplasty which focus on areas with greater than 50% stenosis, rarely remove vulnerable plaques or reduce the incidence of acute coronary syndrome. Technology: The inventions are a portfolio of improved methods and devices for the detection and treatment of vulnerable plaque lesions, best described as ''seek and destroy'' approaches for disease management. Future commercial products will enable clinicians to focus their efforts on those regions in coronary arteries containing atherosclerotic plaques that are most likely to rupture and lead to sudden-onset patient morbidity and mortality. 1. Methods for detection of vulnerable plaque The patent applications provide method of use claims for selectively targeting imaging agents to components of vulnerable plaques, such as inflammatory cells, chemotactic peptides, proteases, glycoproteins, antibodies, and lipids, and thus, advantageously differentiating between the types of atherosclerotic plaques in patients. Differences in probe concentration between normal tissue and tissue at high risk for rupture are characterized using standard photon detection systems optimized for the particular imaging agent (i.e. PDT, SPECT, or PET systems). Enhanced imaging and detection refinements can be achieved through simultaneous usage of described probe combinations and imaging modalities. Applications: - Methodologies to distinguish between vulnerable vs. stable atherosclerotic plaque - Continuous monitoring of plaque progression in at risk patients through repeated imaging - Fluorescent and/or nuclear compositions to selectively identify vulnerable plaque - Diagnostic devices that detect fluorescent or nuclear signals targeted to vulnerable plaque A. Photodynamic therapy (PDT) detection In one aspect, PDT photosensitizer, fluorescent or photoactive compounds are targeted for binding to shoulder macrophages, lymphocytes, or smooth muscle cells in vulnerable plaque, preferably coupled to ligands that bind to surface scavenger receptors. Alternatively, the PDT compositions are targeted to increased lipid populations in the plaque core or proteases found in the fibrous cap. The PDT compositions can be standard dyes known in the art or derivatives made through linkage to macromolecular targeting carriers (e.g. growth factors, microspheres, liposomes, peptides, antibodies, or lipoproteins). Multiple PDT compounds (chlorin-e6 conjugates) have been used successfully by the inventors to selectively detect lesions in rabbit model systems analogous to vulnerable plaque in humans. In the preferred embodiment, photoactivation is carried out using a specifically designed intravascular device that delivers excitation light to the plaque surface inside the artery and receives emitted fluorescence signals which are transmitted to an analysis instrument. Advantages: - Allows potential diagnosis of high-risk patients for sudden-onset coronary disease - Local detection of targeted light allows precise pin-pointing of at risk areas B. Nuclear detection In another aspect, radionuclide (beta or gamma emitters) or paramagnetic contrast imaging agents are coupled to similar macromolecular targeting carriers and/or the PDT compounds described above that localize to the vulnerable or actively forming plaque components. The labeled imaging agents are small molecules that rapidly (less than 6 hours) localize, selectively and irreversibly, to the sites of the lesion. Pending claims cover methods of use, methods of process, and kits for plaque imaging agents coupled to nuclear compounds. The beta emitting agents can be administered alone or in conjunction with the PDT compounds. Both beta and gamma radionuclide detection probes (18F-FDG, 99mTc-fMet-Leu-Phe, 99mTc-Ap4A) have been used successfully by the inventors to selectively detect lesions in rabbit model systems analogous to vulnerable plaque in humans. - Gamma-labeled probes enable non-invasive diagnosis to screen general patient populations - Local detection of photon signals from beta-labeled agents allows precise pin-pointing of plaques - Allows diagnosis of high-risk patients for sudden-onset coronary disease 2. Methods for therapy of vulnerable plaques Additional methods of use claims (i.e. PDT or nuclear agents) are protected in pending patent applications which prevent plaque rupture either by stabilizing the structure of existing components or specifically eliminating the destabilizing populations of inflammatory cells, lipids, or proteases. The patent portfolio also provides coverage for both compositions and methods of use claims of combined intravascular devices which can identify vulnerable plaques via detection of localized fluorescence, temperature, or nuclear signals and then deliver treatment to the patient during the same procedure. The devices minimize patient and physician procedure times leading to improved safety and cost benefits. Enhanced device development through incorporation of multiple diagnostic and therapeutic modalities could potentially lead to further improvements in the identification and treatment rates for vulnerable plaques. Applications: -· Fluorescent and/or nuclear compositions for treatment vulnerable plaque lesions · Devic
Tech Type:		Diagnostics/Biomarkers \| Medical Devices
URL:		http://www.partners.org/techtransfer/availabletechnologies/default.asp
Contact:		Emy Chen, echen4@partners.org, 617-954-9347
Organization:		Massachusetts General Hospital

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