CRISPR-Edited Mi.III Antigen Mouse Model for Hypertension Drug Selection
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Solution Overview
Problem
Current drug development for hypertension relies heavily on in vitro systems that fail to accurately reflect in vivo conditions due to the multi-factorial nature of hypertension, leading to high failure rates.
Innovation Solution
Development of a genetically modified mouse model expressing the human Miltenberger blood group antigen subtype III (Mi.III antigen) through CRISPR/Cas9-mediated genome editing, allowing for the insertion of a transgene encoding Mi.III antigen into the mouse's GYPA gene, which mimics human hypertension conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If in vitro systems are used for hypertension drug research, then the research process is simple and fast, but the accuracy of reflecting in vivo conditions is poor leading to high failure rate
Solution Approach 1:
The patent creates a transgenic mouse model that copies human hypertension pathology by introducing human-specific genetic modifications (humanized ACE gene with human promoter and humanized angiotensinogen gene) into the mouse genome. This copying of human disease characteristics into an animal model allows in vivo testing that accurately reflects human physiological responses, thereby improving drug development accuracy while maintaining the efficiency of animal-based testing.
2Reliability
If a genetically modified mouse model is developed, then the accuracy of reflecting human hypertension conditions is improved, but the complexity of the production process increases
Solution Approach 1:
The patent segments the genetic modification process into distinct components: (1) humanized ACE gene modification with human promoter insertion, (2) humanized angiotensinogen gene modification, and (3) controlled breeding to establish stable transgenic lines. This segmentation of the complex genome editing process into manageable stages allows for systematic optimization and validation at each step, reducing overall process complexity.
Solution Approach 2:
The patent uses a controlled breeding program as an intermediary step between genome editing and final model validation. The F0, F1, and F2 generation breeding scheme serves as a mediator to stabilize the transgenic characteristics and eliminate potential off-target effects, thereby simplifying the path to obtaining a reliable animal model.
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 Mi.III antigen mouse model provides a more accurate and efficient means to identify anti-hypertension drugs by measuring blood pressure changes in response to drug candidates, enhancing the drug selection process.
Implementation Method 1
Development of a genetically modified mouse model expressing the human Miltenberger blood group antigen subtype III (Mi.III antigen) through CRISPR/Cas9-mediated genome editing
Data Source
AI summary
Disclosed herein is a genetically modified mouse whose genome comprises a transgene encoding a Miltenberger blood group antigen subtype III (Mi.II antigen). According to embodiments of the present disclosure, the Mi.III antigen comprises the amino acid sequence of SEQ ID NO: 1. Also disclosed herein are a method of producing the genetically modified mouse, and uses of the genetically modified mouse in selecting a drug candidate for treating hypertension.