TFPI Aptamers Modulate Coagulation via Intermediary Binding

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Solution Overview

Problem

Current treatments for bleeding disorders, such as hemophilia, face challenges with the short half-life of recombinant factors, high costs, and the development of antibody responses, limiting their effectiveness and requiring frequent injections.

Innovation Solution

Development of aptamers that specifically bind to tissue factor pathway inhibitor (TFPI), which can be used alone or in combination with other therapies to modulate coagulation, thereby addressing the limitations of existing treatments by potentially reducing bleeding complications and improving coagulation profiles.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If recombinant coagulation factors are used to treat bleeding disorders, then coagulation function is improved, but treatment frequency increases due to short half-life

Engineering Contradiction:

Improvecoagulation functionVSAvoidhalf-life of recombinant factors

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent uses aptamers as intermediary molecules that bind to TFPI (tissue factor pathway inhibitor) to modulate its activity. These aptamers serve as mediators between the therapeutic goal (improved coagulation) and the biological system, allowing indirect control of coagulation pathways without directly administering long-lived coagulation factors.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the pharmacokinetic parameters of TFPI binding by using aptamers with high affinity and specificity. By altering the binding parameters (affinity, specificity) of the aptamer-TFPI interaction, the therapeutic effect is extended beyond the limitations of recombinant factor half-life.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If recombinant coagulation factors are administered frequently to maintain efficacy, then coagulation control is improved, but treatment cost increases

Engineering Contradiction:

Improvecoagulation controlVSAvoidtreatment cost

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent employs aptamers which are chemically synthesized nucleic acid molecules that can be produced more cost-effectively than recombinant protein factors. Although aptamers themselves have limited circulation half-life, their lower manufacturing cost and potential for prolonged therapeutic effect through TFPI modulation make them an economically favorable alternative to frequent recombinant factor administration.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Duration of action of moving object

If high doses of recombinant factors are used to extend duration of action, then treatment frequency is reduced, but risk of thrombotic complications increases

Engineering Contradiction:

Improveduration of coagulation effectVSAvoidthrombotic complications

Core Design Contradiction:

Duration of action of moving objectVSObject-affected harmful factors

Solution Approach 1:

The aptamer-based therapy provides a feedback mechanism by specifically targeting TFPI, the natural physiological inhibitor of coagulation. By modulating TFPI activity rather than directly adding coagulation factors, the system creates a balanced feedback loop that extends coagulation duration without the linear dose-response relationship that leads to thrombotic risk with recombinant factors.

Inventive Principle:

Principle #23Feedback

4Reliability

If recombinant coagulation factors are used repeatedly, then coagulation function is maintained, but antibody responses develop reducing effectiveness

Engineering Contradiction:

Improvecoagulation functionVSAvoideffectiveness of treatment

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

Instead of administering coagulation factors directly (the conventional approach), the patent inverts the strategy by administering aptamers that modulate the activity of TFPI, the inhibitor of coagulation. This indirect approach avoids the immune system recognizing and attacking foreign coagulation proteins, thereby preventing antibody formation while maintaining coagulation function.

Inventive Principle:

Principle #13The other way round (Inversion)

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

The TFPI aptamers demonstrate the ability to bind with high specificity and affinity, offering a novel approach to manage bleeding disorders by enhancing coagulation and reducing the frequency of injections, while minimizing side effects and costs.

Implementation Method 1

An aptamer is an isolated or purified nucleic acid that binds with high specificity and affinity to a target through interactions other than Watson-Crick base pairing

Methodology Applied

Scientific EffectSpecific binding: Absorption (physical)

Data Source

PatentUS8598327B2Aptamers to tissue factor pathway inhibitor and their use as bleeding disorder therapeutics

Publication Date: 2013.12.03 BAXALTA GMBH

AI summary

The invention relates generally to the field of nucleic acids and more particularly to aptamers that bind to TFPI, which are useful as therapeutics in and diagnostics of bleeding disorders and/or other diseases or disorders in which TFPI has been implicated. In addition, the TFPI aptamers may be used before, during and/or after medical procedures to reduce complications or side effects thereof. The invention further relates to materials and methods for the administration of aptamers that bind to TFPI.