Uromodulin Polypeptide Inhibits Vascular Calcification

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Solution Overview

Problem

Current treatments are ineffective in preventing or halting the progression of vascular calcification, a condition associated with increased cardiovascular mortality, particularly in patients with chronic kidney disease, where phosphate promotes extensive calcifications and inflammation.

Innovation Solution

Uromodulin polypeptides, characterized by specific amino acid sequences and biological activity, are used to inhibit vascular calcification by targeting vascular smooth muscle cells and reducing osteogenic transformation, and are administered through pharmaceutical compositions or nucleic acid expression systems to enhance stability and bioavailability.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Quantity of substance

If phosphate is present in the system, then vascular calcification is promoted, but cardiovascular mortality increases

Engineering Contradiction:

Improvephosphate concentrationVSAvoidvascular calcification

Core Design Contradiction:

Quantity of substanceVSObject-affected harmful factors

Solution Approach 1:

Uromodulin acts as an intermediary substance that binds to calcium and phosphate, preventing their direct interaction and subsequent calcification. The protein serves as a mediator that sequesters these minerals in a non-toxic form, thereby protecting vascular tissue from calcification while maintaining physiological phosphate levels.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention converts the harmful effect of phosphate (which promotes calcification) into a beneficial outcome by using uromodulin to bind phosphate and calcium together. This transforms the toxic calcium-phosphate interaction into a controlled complex that prevents pathological calcification while maintaining mineral homeostasis.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

2Reliability

If vascular smooth muscle cells undergo osteogenic transformation, then calcification progresses, but therapeutic options remain limited

Engineering Contradiction:

Improvecalcification progressionVSAvoidtherapeutic agent availability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Uromodulin exerts its protective effect through self-service mechanisms where the protein naturally binds calcium and phosphate in the circulation, preventing their deposition in vascular tissue without requiring active intervention in the osteogenic transformation process. The substance autonomously performs its calcification-preventing function.

Inventive Principle:

Principle #25Self-service

Solution Approach 2:

The invention changes the biochemical parameters of the system by introducing uromodulin, which alters the solubility and binding characteristics of calcium and phosphate. This parameter change prevents the supersaturation conditions that lead to calcification, thereby interfering with the osteogenic transformation process.

Inventive Principle:

Principle #35Parameter changes

3Object-affected harmful factors

If uromodulin is administered, then vascular calcification is inhibited, but systemic circulation levels must be maintained

Engineering Contradiction:

Improvevascular calcificationVSAvoiduromodulin plasma levels

Core Design Contradiction:

Object-affected harmful factorsVSDuration of action of moving object

Solution Approach 1:

The invention ensures continuous protective action through repeated administration of uromodulin, maintaining sustained plasma levels that continuously prevent calcification. The treatment protocol is designed to keep uromodulin concentrations above the threshold needed for effective calcium-phosphate binding throughout the treatment period.

Inventive Principle:

Principle #20Continuity of useful action

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

Uromodulin effectively prevents and treats vascular calcification by inhibiting osteogenic transformation of smooth muscle cells and reducing inflammation, as demonstrated by its ability to suppress calcification markers and calcification processes in vitro and in vivo, offering a potential therapeutic agent for vascular calcification and associated conditions.

Implementation Method 1

Uromodulin is a powerful inhibitor of vascular calcification... uromodulin binds to calcium and phosphate ions, preventing their crystallization

Methodology Applied

Scientific EffectIon binding: Adsorption

Implementation Method 2

prevention of pathological crystallization... uromodulin binds to calcium and phosphate ions, preventing their crystallization

Methodology Applied

Scientific EffectCrystallization inhibition: Crystallisation

Data Source

PatentEP3589306B1Uromodulin for use in prevention and therapy of vascular calcification or vascular inflammation

Publication Date: 2022.04.27 CHARITE UNIVS MEDIZIN BERLIN

Figure 1A~1E
Figure 2A~2D
Figure 3A~3B

AI summary

The invention relates to the use of a uromodulin polypeptide in prevention or therapy of vascular calcification or a disease caused by, or related to, vascular calcification, particularly vascular calcification in chronic kidney disease, in diabetes, in aging and in atherosclerosis.