Efferocytosis Agents Stabilize Atherosclerotic Plaque Necrotic Cores
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Solution Overview
Problem
Atherosclerotic cardiovascular disease (ASCVD) remains a significant cause of morbidity and mortality, with existing treatments failing to effectively prevent recurrence and mortality, particularly due to the complex interaction of genetic and environmental factors, and the presence of risk-associated polymorphisms like the 9p21 locus, which contribute to atherosclerotic plaque instability and progression.
Innovation Solution
Administering agents that increase efferocytosis of apoptotic smooth muscle cells in individuals with the 9p21 risk allele, such as those that activate CDKN2B, mimic calreticulin, or reduce the interaction between CD47 and SIRPα, to stabilize and prevent atherosclerotic plaque formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional risk factor treatments are used, then some cardiovascular risk is reduced, but recurrence and mortality rates remain high (2-4% per year)
Solution Approach 1:
The patent changes the biological parameter of efferocytosis activity by administering agents that enhance this process. Specifically, it targets the CD47-SIRPα interaction pathway and modulates CDKN2B expression to improve apoptotic cell clearance, thereby stabilizing atherosclerotic plaques and reducing cardiovascular events beyond traditional risk factor management
Solution Approach 2:
The patent introduces intermediary substances (agents) that mediate between the genetic risk factors and the disease outcome. These agents enhance efferocytosis by interacting with CD47 and SIRPα, serving as a bridge to overcome the harmful effects of the 9p21 risk allele and other genetic factors
2Reliability
If efferocytosis is enhanced to stabilize plaques, then plaque vulnerability is reduced, but the mechanism becomes more complex
Solution Approach 1:
The patent extracts and targets a specific critical component of the efferocytosis pathway - the CD47-SIRPα interaction. By focusing on this specific molecular mechanism rather than the entire complex efferocytosis process, it simplifies the therapeutic approach while maintaining effectiveness in stabilizing plaques
Solution Approach 2:
The patent segments the complex efferocytosis pathway into manageable targets, specifically identifying CD47, SIRPα, and CDKN2B as key components. This segmentation allows for targeted intervention at specific points in the pathway, making the complex biological process more tractable for therapeutic development
Data Source
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AI summary
Smooth muscle cells (SMC) from subjects carrying at least one 9p21 risk factor, can be resistant to efferocytosis, leading to the retention of such cells in the necrotic core of atherosclerotic plaque. In the methods of the invention, an agent that increases efferocytosis of cellular components of coronary plaque, including efferocytosis of apoptotic smooth muscle cells, is administered to the subject in a dose and for a period of time effective to stabilize, prevent or reduce atherosclerotic plaque in the individual.