Humanized CD27 Mouse Models for Accurate Drug Screening
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Solution Overview
Problem
Conventional drug development methods using in vitro screening and conventional experimental animals fail to accurately reflect human disease states and interactions, leading to high failure rates and increased costs in clinical trials due to the inability to replicate the human body environment and tumor microenvironment.
Innovation Solution
Development of genetically modified animal models expressing human or chimeric CD27 proteins, allowing for the creation of a platform for drug screening and evaluation that mimics human CD27 target sites, enabling more accurate pharmacological testing and reducing development costs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional experimental animals are used for in vivo pharmacological testing, then animal testing is simpler and faster, but the test results do not accurately reflect human disease states and interactions
Solution Approach 1:
The patent creates humanized mouse models by replacing the endogenous mouse CD27 gene with the human CD27 gene, allowing the mouse to express human CD27 protein. This copying of the human gene into the animal model enables the model to accurately reflect human disease states and drug interactions while maintaining the simplicity of animal testing.
Solution Approach 2:
The patent modifies the genetic parameter of the mouse model by introducing human CD27 gene sequences at the endogenous mouse CD27 locus. This parameter change (from mouse to human gene) enables the model to exhibit human-like biological responses to drugs, improving measurement precision without requiring complete human subject testing.
2Reliability
If in vitro screening approaches are used, then screening process is simpler and faster, but the screening cannot provide body environment context leading to higher failure rate
Solution Approach 1:
The humanized mouse model serves as an intermediary system between in vitro screening and human clinical trials. It provides the body environment context (immune system, tumor microenvironment, stromal cells) that in vitro systems lack, while being simpler and more controllable than human subjects. This intermediary enables reliable drug screening with reduced failure rate.
Solution Approach 2:
The humanized mouse model performs multiple functions: it serves as a living model for drug screening, provides a platform for studying human disease mechanisms, enables evaluation of drug interactions in a whole-body context, and predicts clinical trial outcomes. This multi-functionality increases reliability without requiring separate testing systems for each purpose.
3Measurement precision
If humanized animal models are developed, then drug screening accuracy improves, but development time and cost increase
Solution Approach 1:
The patent employs preliminary actions by using established gene targeting techniques and existing mouse strain infrastructure to create humanized models. The endogenous gene replacement strategy is pre-planned and can be executed efficiently using standardized protocols, reducing the time needed compared to creating entirely new model systems from scratch.
4Ease of manufacture
If conventional animal models are used, then testing is more cost-effective, but clinical trial results differ significantly from animal results
Solution Approach 1:
The patent changes the genetic parameter from mouse to human CD27 gene, enabling the animal model to exhibit human-specific biological characteristics. This parameter change allows the model to predict human clinical outcomes accurately while maintaining the cost efficiency of animal testing, as humans cannot be tested in the same controlled manner.
Data Source
AI summary
The present disclosure relates to genetically modified non-human animals (e.g., genetically-modified mice) that express a human or chimeric (e.g., humanized) CD27. The present disclosure also relates to methods of generating the genetically-modified animals (e.g., genetically modified mice), and methods of using the genetically modified non-human animals (e.g., genetically modified mice) described herein.