TREM-2 Agonist Therapy for Marfan Aortic Wall Stabilization
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Solution Overview
Problem
Current treatments for Marfan syndrome, particularly for aortic dilatation and dissection, are limited, and the pathophysiological mechanisms causing these complications are not well understood, with a high morbidity and mortality rate.
Innovation Solution
The use of TREM-2 agonists, specifically antibodies that activate the Triggering Receptor Expressed on Myeloid cells 2 (TREM-2), to modulate immune-inflammatory responses and potentially stabilize the aortic wall in Marfan syndrome.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If beta-blockers are used to limit aortic dilatation, then aortic growth is reduced, but treatment options remain limited and morbidity/mortality remain high
Solution Approach 1:
The patent changes the therapeutic parameter from beta-blockade to TREM-2 activation, representing a fundamental shift in the mechanism of action. This allows for new treatment approaches that target different pathophysiological pathways in Marfan syndrome, specifically addressing aortic wall degradation through immune modulation rather than just hemodynamic control
Solution Approach 2:
The patent introduces TREM-2 agonists as intermediary molecules that mediate between the immune system and aortic wall integrity. These agonists act as intermediaries to recruit and activate macrophages that can clear debris and promote tissue repair, bridging the gap between immune response and structural stabilization
2Reliability
If Losartan is used to improve arterial wall architecture, then aortic dilatation is reduced in animal models, but beneficial impact in humans remains controversial
Solution Approach 1:
The patent employs TREM-2 agonists to enable the body's own immune system to serve the therapeutic function. By activating endogenous macrophages through TREM-2, the treatment leverages the body's intrinsic repair mechanisms rather than relying on external pharmacological agents with uncertain human efficacy
Solution Approach 2:
The patent replaces the mechanical/structural approach of AT1R blockade with a biological/immunological approach. Instead of mechanically blocking receptor signaling, the treatment uses immunomodulation to activate protective macrophage functions, substituting one therapeutic mechanism for another more precisely targeted at the underlying pathology
3Object-affected harmful factors
If surgical treatment is performed when aortic diameter exceeds 50 mm, then aortic rupture risk is reduced, but significant perioperative complications occur
Solution Approach 1:
The patent applies preliminary therapeutic action by using TREM-2 agonists to stabilize the aortic wall and reduce dilatation progression before surgical intervention becomes necessary. This pre-treatment strengthens the aortic wall and may delay or reduce the need for surgery, thereby avoiding perioperative complications
Solution Approach 2:
The patent provides beforehand cushioning by activating protective macrophage functions that can prevent or mitigate further aortic wall degradation. This creates a protective effect that cushions against the progression to critical aortic dimensions, reducing the urgency and risk associated with surgical intervention
Data Source
AI summary
Marfan syndrome is caused by mutations in the FBN1 gene (15q21) that codes for Fibrillin-1, an essential connective tissue protein and is a pathology responsible for a high morbidity and mortality. Apart from surgery, treatment options are limited. It is therefore essential to develop new pharmacological approaches to limit aortic dilatation and/or rupture. The inventors have demonstrated a critical role for TREM-2 in the pathophysiology of ascending aortopathy related to Marfan disease. Deletion of TREM-2 indeed aggravates ascending aorta dilation and rupture. Stimulating TREM-2 receptor with peptide or agonistic monoclonal antibody represent a new therapeutic approach for Marfan syndrome.