Humanized IL1RAP Animal Models for Autoimmune Disease Research
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Solution Overview
Problem
Current animal models lack the ability to effectively study the function of human IL1RAP and its role in autoimmune diseases and tumors due to differences in IL1RAP expression between humans and animals, limiting the accuracy of drug testing and treatment efficacy assessments.
Innovation Solution
Development of genetically modified non-human animals that express human or chimeric IL1RAP, allowing for the creation of animal models with humanized IL1RAP genes integrated into their genome, either by replacing or inserting sequences encoding human IL1RAP at the endogenous IL1RAP locus, enabling the expression of humanized IL1RAP proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional animal models are used, then the model is simple and easy to maintain, but the accuracy of studying human IL1RAP function is poor due to species differences
Solution Approach 1:
The patent changes the genetic parameter of the animal model by replacing or inserting human IL1RAP sequences into the endogenous IL1RAP locus, transforming the animal from expressing endogenous IL1RAP to expressing humanized IL1RAP. This parameter change resolves the contradiction by improving the accuracy of human IL1RAP function studies while maintaining the animal model framework.
Solution Approach 2:
The patent creates a copy of the human IL1RAP gene and integrates it into the animal genome at the endogenous IL1RAP locus. This copying approach allows the animal to express human IL1RAP protein, thereby improving the accuracy of human disease modeling without requiring complete replacement of the animal system.
2Reliability
If human IL1RAP sequences are integrated into animal genome, then the representation of human IL1RAP function is improved, but the genetic modification complexity increases
Solution Approach 1:
The patent segments the human IL1RAP gene into specific sequences (exons 2-9) and integrates them into the animal genome at the endogenous IL1RAP locus. This segmentation approach allows for controlled genetic modification that improves reliability of drug testing while managing the complexity through targeted integration rather than complete genome replacement.
Solution Approach 2:
The endogenous IL1RAP locus serves as an intermediary site for integrating human IL1RAP sequences. By using the existing animal genome structure as a mediator, the patent achieves reliable human IL1RAP expression while simplifying the genetic modification process compared to de novo gene insertion.
3Manufacturing precision
If endogenous IL1RAP is replaced with human IL1RAP, then the humanized protein expression is achieved, but the loss of endogenous IL1RAP expression occurs
Solution Approach 1:
The patent changes the expression parameter from endogenous to humanized IL1RAP by replacing or inserting human sequences at the endogenous locus. This parameter change achieves precise humanized protein expression while the endogenous IL1RAP loss is acceptable because the humanized version fulfills the research requirement for human-specific function studies.
Data Source
AI summary
Provided are genetically modified animal expressing human or chimeric (e.g., humanized) IL1RAP, and methods of use thereof.