Tissue-Specific Wnt Enhancers for Targeted Receptor Stabilization

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Solution Overview

Problem

Existing Wnt signaling modulation technologies lack tissue-specificity, leading to non-specific effects across various tissues due to the widespread expression of Wnt ligands and receptors, necessitating a need for targeted enhancement strategies.

Innovation Solution

Development of tissue-specific Wnt signal enhancing molecules comprising a domain that binds E3 ubiquitin ligases ZNRF3 or RNF43 and a tissue-specific cell surface receptor, stabilizing Wnt receptors and enhancing signaling through internalization or sequestration, using fusion proteins, antibodies, or small molecules.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If R-spondins are used to enhance Wnt signaling, then Wnt signal amplification is achieved, but tissue-specificity is lost due to widespread expression of LGR4-6 and ZNRF3/RNF43

Engineering Contradiction:

ImproveWnt signal amplificationVSAvoidnon-specific effects across tissues

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by creating chimeric proteins where the R-spondin molecule is modified to contain a tissue-specific targeting domain fused to the Wnt-binding domain. This allows the same R-spondin derivative to selectively bind and enhance Wnt signaling only in tissues expressing the specific cell surface receptor, thereby achieving local enhancement while avoiding non-specific effects in other tissues.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent uses tissue-specific cell surface receptors as intermediaries to deliver the Wnt signal enhancement effect selectively to target tissues. The chimeric R-spondin molecule binds to these receptors, which are only present on specific cell types, thereby mediating the enhancement effect locally rather than systemically throughout all tissues expressing ZNRF3/RNF43.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If Wnt signaling is enhanced systemically, then bone formation and tissue regeneration are promoted, but off-target effects occur in multiple tissues

Engineering Contradiction:

Improvetissue regeneration rateVSAvoidoff-target effects

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The invention modifies R-spondin to have tissue-specific quality by fusing it with a domain that recognizes and binds to a cell surface receptor uniquely or preferentially expressed in the target tissue (e.g., liver, bone, oral mucosa). This ensures that the productivity benefit of enhanced Wnt signaling is localized only to tissues expressing the target receptor, preventing off-target effects in other tissues.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent changes the binding specificity parameter of the R-spondin molecule by engineering chimeric structures with different domain compositions. This allows the same basic R-spondin scaffold to be tailored for different tissue targets by changing which cell surface receptor it binds to, thereby controlling the spatial distribution of the therapeutic effect.

Inventive Principle:

Principle #35Parameter changes

3Adaptability or versatility

If multiple Wnt ligands and receptors are present, then signaling versatility is achieved, but specificity for targeted tissue modulation is reduced

Engineering Contradiction:

ImproveWnt signaling capacityVSAvoidtissue targeting precision

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The patent introduces tissue-specific cell surface receptors as intermediary targets to achieve precise tissue routing of the Wnt signal enhancement effect. While the system maintains versatility through the ability to target different receptors in different tissues, the use of these specific intermediaries ensures that each intervention is precisely localized to the intended tissue, resolving the conflict between versatility and precision.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The chimeric R-spondin platform provides universality by being applicable to multiple different tissue targets through engineering different binding domains. The same basic construct design can be adapted to target various cell surface receptors, making the approach universally applicable across different tissues while maintaining high targeting precision for each specific application.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

Achieves tissue-specific enhancement of Wnt signaling, effectively treating and preventing diseases by stabilizing Wnt receptors and increasing signaling in targeted tissues, such as liver, bone, and oral mucosa, while minimizing off-target effects.

Implementation Method 1

comprising a domain that binds an E3 ubiquitin ligase, ZNRF3 or RNF43

Methodology Applied

Scientific EffectUbiquitin ligase binding:

Implementation Method 2

mediating tissue-specific internalization or sequestration of the E3 ligases, ZNRF3/RNF43

Methodology Applied

Scientific EffectReceptor internalization:

Implementation Method 3

stabilizing Wnt receptors and enhancing Wnt signaling

Methodology Applied

Scientific EffectProtein stabilization:

Data Source

PatentUS12466884B2Tissue-specific WNT signal enhancing molecules and uses

Publication Date: 2025.11.11 SURROZEN OPERATING INC

AI summary

The present disclosure provides tissue-specific Wnt signal enhancing molecules, and related methods of using these molecules to increase Wnt signaling in liver tissues.