Humanized Transgenic Mice for IL-17A Drug Screening
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Solution Overview
Problem
Current animal models, such as mice, are inadequate for studying human IL-17/IL-17R signaling pathways due to significant differences in amino acid sequences, limiting the effectiveness of pre-clinical trials and drug development for autoimmune diseases, as antibodies targeting human IL-17A do not recognize mouse IL-17A, necessitating the development of non-human animal models expressing humanized proteins associated with this pathway.
Innovation Solution
Genetically modified non-human animals, specifically mice, are created to express human IL-17A, IL-17RA, and TNF-alpha genes, allowing for the production of humanized proteins that can be used to develop more effective disease models and screen agents targeting the IL-17/IL-17R signaling pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If regular mice are used for pre-clinical trials, then the animal model is simple and easy to maintain, but the amino acid sequence differences prevent antibodies from recognizing the target protein, making the model inadequate for studying human IL-17/IL-17R signaling pathways
Solution Approach 1:
The patent changes the genetic parameters of the mouse by introducing human IL-17A and human IL-17RA genes into the mouse genome. This creates a humanized mouse model where the expressed proteins have human amino acid sequences, allowing antibodies to recognize the target. The genetic parameter change (from mouse sequences to human sequences) resolves the recognition problem while maintaining the mouse as the host organism.
Solution Approach 2:
The patent uses an intermediary approach by creating a hybrid organism that combines mouse biology with human protein expression. The mouse serves as the host (intermediary) that carries and expresses the human genes, bridging the gap between simple mouse models and human disease modeling. This intermediary model allows human-specific antibodies to function in a live animal system.
2Measurement precision
If humanized mouse models are created to express human proteins, then the model accuracy for drug screening improves, but the genetic modification process becomes more complex and time-consuming
Solution Approach 1:
The patent employs preliminary action by pre-establishing the humanized mouse model with properly integrated human genes before conducting drug screening studies. The genetic modification, gene expression validation, and model characterization are performed in advance, creating a ready-to-use model system. This preliminary setup, though time-consuming initially, enables efficient and accurate drug screening thereafter without repeating the complex genetic work for each study.
3Reliability
If antibodies are developed to target human IL-17A, then the therapeutic effectiveness improves, but the antibodies cannot recognize mouse IL-17A due to sequence differences, limiting pre-clinical evaluation
Solution Approach 1:
The patent changes the antigenic parameter of the target protein by expressing human IL-17A in the mouse model. This parameter change (amino acid sequence composition) makes the target protein compatible with human-specific antibodies. The expressed human protein has the correct epitopes that human antibodies recognize, while the mouse host provides the physiological environment for studying disease and treatment response.
Data Source
AI summary
Provided are a humanized transgenic non-human animal, especially a rodent, in particular a transgenic mouse containing a human interleukin 17A (IL-17A) gene, a human gene 17RA (IL-17RA) and/or a human TNF-alpha gene, and a preparation method therefor and the use thereof.