Humanized Protein C Transgenic Mice for Therapeutic Testing
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Solution Overview
Problem
The lack of viable genetically modified non-human animals expressing human Protein C due to neonatal lethality of mice lacking protein C and inefficient function of human Protein C in mouse plasma hinders comprehensive in vivo studies for therapeutic agent testing.
Innovation Solution
Generation of genetically modified mice where both copies of the endogenous nucleotide sequence encoding Protein C are replaced with a nucleotide sequence encoding human Protein C, enabling expression of functional human Protein C fragments or variants, making them suitable models for testing therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If mice lacking endogenous protein C are generated to study human Protein C, then the model would be useful for therapeutic testing, but the mice exhibit neonatal lethality
Solution Approach 1:
The invention replaces the endogenous mouse Protein C gene with the human Protein C gene sequence, changing the genetic parameter to produce mice that express human Protein C instead of mouse Protein C. This allows the mice to be viable while serving as appropriate models for studying human Protein C function and testing therapeutic agents.
2Adaptability or versatility
If human Protein C is expressed in mice, then the model would be relevant for human therapy, but human Protein C does not function efficiently in mouse plasma
Solution Approach 1:
The invention replaces the entire endogenous mouse Protein C gene with the human Protein C gene, ensuring that mice express human Protein C with human plasma compatibility. This genetic parameter change allows human Protein C to function efficiently in the mouse system, making the model relevant for human therapy while maintaining functional efficiency.
Data Source
Figure 1A~1B
Figure 1C~1D
Figure 2
AI summary
The present invention relates generally to genetically modified non-human animals. The present invention relates to a genetically modified non-human animal, in which at least one copy of the endogenous nucleotide sequence encoding Protein C in the genome of said non-human animal has been replaced by a nucleotide sequence encoding human Protein C, encoding a functional fragment of human Protein C or encoding a functional variant of human Protein C. The invention also relates to vectors, cells and methods for the production of such non-human animals. The invention also relates to methods of testing agents for their ability to alter to the level and/or functional activity of human protein C and thus provides methods of testing agents for their potential therapeutic efficacy.