Wnt Signaling Agonists via RECK GPR124 Mediator

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Solution Overview

Problem

Current therapies for neurovascular disorders and CNS disorders involving neurovascular dysfunction lack specificity in stimulating Wnt/β-catenin signaling, often causing cross-reactivity with other Frizzled pathways, which can lead to unintended consequences.

Innovation Solution

Development of a Wnt decoding module that utilizes RECK and GPR124 to selectively activate Wnt7-specific signaling through the formation of RECK/GPR124/Frizzled/LRP signalosomes, allowing for targeted activation of Wnt/β-catenin signaling in cerebral endothelial cells without affecting other pathways.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapies stimulate Wnt/β-catenin signaling, then treatment efficacy for neurovascular disorders is improved, but cross-reactivity with other Frizzled pathways occurs causing unintended consequences

Engineering Contradiction:

Improvetreatment efficacyVSAvoidcross-reactivity with other Frizzled pathways

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The invention introduces Gpr124 as an intermediary component that specifically binds Wnt7 and recruits it to Frizzled receptors. This intermediary mechanism ensures that only Wnt7-specific signaling is activated through the Gpr124-Frizzled-Wnt7 complex, preventing cross-reactivity with other Frizzled pathways while maintaining reliable Wnt/β-catenin signaling activation for treating neurovascular disorders

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention creates a localized signaling complex with specific composition (Gpr124-Frizzled-Wnt7) that confers pathway selectivity. The local assembly of this specific triplet complex ensures that Wnt7 signaling is activated only at sites where all three components are present, providing spatial and molecular specificity that prevents off-target effects on other Frizzled pathways

Inventive Principle:

Principle #3Local quality

2Reliability

If Wnt/β-catenin signaling is activated in cerebral endothelial cells, then neurovascular dysfunction is treated, but other Frizzled pathways may be inadvertently affected

Engineering Contradiction:

Improveneurovascular treatment efficacyVSAvoidunintended effects on other pathways

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

Gpr124 serves as a pathway-specific intermediary that physically links Wnt7 to Frizzled receptors in a selective manner. This intermediary ensures that cerebral endothelial cells receive targeted Wnt7 signals through the Gpr124-Frizzled-Wnt7 complex without activating other Frizzled pathways, thereby treating neurovascular dysfunction while avoiding unintended effects

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention segments the Wnt signaling system into distinct pathway-specific complexes. By creating a dedicated Gpr124-Frizzled-Wnt7 signaling module separate from other Wnt-Frizzled interactions, the system allows selective activation of Wnt/β-catenin signaling in cerebral endothelial cells independent of other Frizzled pathway activities

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS20240092848A1WNT signaling agonist molecules

Publication Date: 2024.03.21 UNIV LIBRE DE BRUXELLES

AI summary

Therapeutic agents are capable of activating (GPR)124/RECK/Frizzled/lipoprotein receptor-related protein (LRP)-mediated Wnt signaling. The agents do not activate Frizzled/LRP-mediated Wnt signaling in the absence of RECK and/or GPR124. The agents are particularly useful for the prevention or treatment of neurovascular disorders or central nervous system (CNS) disorders that include neurovascular dysfunction.