Humanized IL15 Transgenic Mouse for Immune System Replication
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Solution Overview
Problem
Current animal models, such as immunodeficient mice, have variable engraftment capacities and do not accurately replicate human immune systems, leading to discrepancies in drug efficacy testing and disease modeling.
Innovation Solution
Development of genetically modified animals that express human or chimeric IL15, allowing for enhanced engraftment of exogenous cells and creation of a humanized immune system, facilitating improved drug screening and disease modeling.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunodeficient mice are used as model organisms, then they can be used for immune system research and drug testing, but their engraftment capacity varies and they do not accurately replicate human immune systems
Solution Approach 1:
The patent applies local quality by selectively replacing only the IL15 gene in the mouse genome with the human IL15 gene, rather than replacing the entire immune system. This localized genetic modification allows the animal to express human IL15 protein specifically, improving human immune system replication accuracy while maintaining the overall mouse immune system structure and acceptable engraftment capacity.
Solution Approach 2:
The patent creates a composite biological system by combining human IL15 gene sequences with mouse genomic DNA. The resulting chimeric animal model contains both human and mouse genetic elements, allowing it to express human cytokines while maintaining mouse physiological characteristics, thus achieving both improved human immune system replication and maintained engraftment capacity.
2Adaptability or versatility
If human IL15 or chimeric IL15 is expressed in non-human animals, then engraftment capacity of exogenous cells is enhanced, but the animal requires genetic modification
Solution Approach 1:
The patent extracts the IL15 gene from the human genome and inserts it into the mouse genome at a specific locus. This extraction and transplantation approach allows for targeted genetic modification that enhances engraftment capacity while minimizing overall genetic complexity, as only a single gene replacement is performed rather than comprehensive genome editing.
3Quantity of substance
If endogenous IL15 is suppressed or knocked out in animals, then human IL15 expression can be enhanced, but the animal may have compromised immune function
Solution Approach 1:
The patent uses the mouse IL15 gene locus as an intermediary site to express human IL15. By replacing the mouse IL15 gene with the human IL15 gene at the same genomic location, the animal maintains the normal regulatory control mechanisms of the IL15 locus while producing human IL15 protein. This approach ensures adequate human IL15 expression levels while preserving immune system functionality through the use of endogenous regulatory elements.
Data Source
AI summary
The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) IL15, and methods of use thereof.