WNT7B-Derived Polypeptides for Bone Formation Without β-Catenin Risk
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Solution Overview
Problem
Current bone formation promoting drugs, such as classical WNT agonists, pose risks of tumorigenesis and severe adverse reactions due to excessive activation of the classical WNT/β-Catenin signaling pathway, limiting their clinical applications.
Innovation Solution
Development of WNT7B-derived polypeptides, specifically composed of the Thumb and index domains of WNT7B protein, which promote bone formation and regeneration without activating the classical WNT signaling pathway, utilizing the Reck/Gpr124/Ca2+/Nfatc1 signaling axis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If classical WNT agonists (such as romosozumab and recombinant WNT3A) are used to promote bone formation, then bone regeneration is enhanced, but the risk of tumorigenesis and severe adverse reactions increases due to excessive activation of the classical WNT/β-Catenin signaling pathway
Solution Approach 1:
The invention segments the WNT7B protein into specific functional domains (Thumb domain: amino acids 1-17 and finger domain: amino acids 19-34) to create a derived polypeptide that selectively activates bone formation pathways while avoiding excessive activation of the classical WNT/β-Catenin signaling pathway, thus reducing tumorigenesis risk
Solution Approach 2:
The derived polypeptide exhibits local quality by specifically targeting bone tissue for formation promotion while having differential effects on other tissues. It activates bone-specific pathways (such as the Reck/Gpr124/Ca2+/Nfatc1 signaling axis) without causing systemic overactivation of WNT signaling that would lead to tumorigenesis
2Productivity
If Teriparatide is used to treat osteoporosis, then bone formation is promoted, but its benefits for fracture healing and bone regeneration remain insufficiently evaluated and limited
Solution Approach 1:
The WNT7B-derived polypeptide demonstrates universality by effectively treating multiple bone-related conditions including osteoporosis, fracture healing, and bone regeneration. It activates multiple beneficial pathways (classical WNT-independent pathways such as Reck/Gpr124/Ca2+/Nfatc1) that confer broad therapeutic benefits across different bone diseases and repair processes
Data Source
AI summary
The present invention belongs to the technical field of biopharmaceutical materials, and specifically relates to a bone formation promoting polypeptide and application thereof. Specifically, the present invention provides a polypeptide or the variant thereof for promoting bone formation, bone regeneration, and bone repair, and/or preventing and/or treating osteoporosis, a fusion protein and a pharmaceutical composition comprising such a polypeptide or the variant thereof, and pharmaceutical use of such a polypeptide or the variant thereof and fusion protein.