Humanized Mouse Model for Anti-Thrombotic Testing
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Solution Overview
Problem
Current drug development for thrombosis lacks an appropriate small animal model to effectively test therapies targeting human platelets due to differences in protein structures and isoforms between mouse and human models, and mouse VWF does not support significant interactions with human platelets, hindering the testing of anti-thrombotic agents.
Innovation Solution
Genetic alteration of mice to express VWF with an amino acid difference found in human VWF-A1 domain, enabling it to support adhesion of human platelets, thus creating a 'humanized' mouse model for pre-clinical testing of drugs and targeted molecular imaging agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If mouse VWF is used in the animal model, then the model is simple and easy to maintain, but it does not support significant interactions with human platelets, making it unsuitable for testing anti-thrombotic agents targeting human platelets
Solution Approach 1:
The patent applies local quality by making a specific amino acid substitution (alanine to threonine at position 1347 in the A1 domain of mouse VWF) to change the binding specificity from mouse platelet-specific to human platelet-specific. This localized modification at a critical binding interface enables human platelet adhesion while maintaining the overall simplicity of the mouse model system.
Solution Approach 2:
The patent changes the amino acid sequence parameter of the VWF protein by substituting alanine with threonine at position 1347. This parameter change alters the biochemical properties of the VWF-A1 domain, enabling it to interact with human platelet GPIbα receptor, thereby transforming the model's compatibility from mouse-specific to human-specific.
2Reliability
If standard mouse models are used for drug testing, then the testing process is simple and cost-effective, but the results cannot be reliably extrapolated to human thrombosis due to species differences in protein structures
Solution Approach 1:
The patent improves reliability by making a localized amino acid substitution at position 1347 in the VWF A1 domain, which is the critical binding interface for platelet interaction. This specific modification ensures that the mouse model accurately reflects human platelet-VWF interactions, making test results relevant to human thrombosis while maintaining the simplicity of mouse genetics.
Solution Approach 2:
The patent creates a humanized version of mouse VWF by copying the critical amino acid sequence from human VWF (threonine at position 1347) into the mouse VWF gene. This allows the mouse model to replicate human platelet adhesion mechanisms, enabling reliable preclinical testing of anti-thrombotic agents before human trials.
3Loss of time
If research progresses to clinical trials without adequate pre-clinical testing in a human-relevant model, then the development timeline is shortened, but the risk of discovering anti-thrombotic effects only in human trials increases
Solution Approach 1:
The patent enables preliminary testing of anti-thrombotic agents in a human-relevant preclinical model before human clinical trials. By creating transgenic mice with human-specific VWF that supports human platelet adhesion, researchers can evaluate drug efficacy and safety regarding hemostatic parameters in advance, reducing the risk of unexpected thrombotic or bleeding effects in human trials.
Solution Approach 2:
The patent allows preliminary identification and mitigation of potential harmful effects (thrombotic or bleeding) of anti-thrombotic agents before human trials. By testing drugs in the humanized mouse model, researchers can detect adverse hemostatic effects early and adjust dosing or formulation to prevent harmful outcomes in human clinical trials.
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
This approach allows for better understanding of human platelet binding mechanisms at vascular injury sites and enables pre-clinical testing of anti-thrombotic agents and imaging agents, facilitating the development of new therapies for thrombosis and hemostasis.
Implementation Method 1
The mutant A1 domain contained within mouse plasma VWF supports the binding of human platelets in vivo and ex-vivo
Data Source
AI summary
The invention provides a transgenic non-human animal expressing von Willebrand Factor A1 protein containing at least one mutation selected from the group consisting of: 1263P>S, 1269N>D, 1274K>R, 1287M>R, 1302G>D, 1308H>R, 1313R>W, 1314I>V, 1326R>H, 1329L>I, 1330E>G, 1333A>D, 1344T>A, 1347I>V, 1350T>A, 1370G>S, 1379H>R, 1381T>A, 1385T>M 1391P>Q, 1394A>S, 1397L>F, 1421S>N, 1439L>V, 1442G>S, 1449R>Q, 1466A>P, 1469Q>L, 1472Q>H, 1473V>M, 1475H>Q, 1479S>G, and any combination thereof.