Humanized Transgenic Animals for Accurate Drug Evaluation
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Solution Overview
Problem
Current transgenic animal models expressing only one human gene are insufficient for effectively evaluating drug candidates targeting human diseases, as they do not accurately replicate the protein-protein interactions underlying human physiological processes, leading to potential drug failures in clinical trials due to species-specific protein differences.
Innovation Solution
Development of transgenic animals expressing at least two human proteins that dynamically interact, with the goal of mimicking human disease pathways, where the human proteins form part of a cascade of signaling pathways, and the endogenous animal genes are silenced or replaced to ensure accurate human protein function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Device complexity
If transgenic animals expressing only one human gene are used, then the complexity of the animal model is reduced, but the accuracy of mimicking human protein-protein interactions deteriorates
Solution Approach 1:
The patent combines multiple human genes (at least two human genes encoding proteins that interact with each other) into a single transgenic animal model. This merging approach allows the animal to express multiple human proteins that can interact with each other and with endogenous animal proteins, thereby accurately replicating human protein-protein interaction networks while maintaining a unified animal model system.
Solution Approach 2:
The transgenic animal model is designed to serve multiple functions: it expresses human proteins that interact with each other, interacts with endogenous animal proteins, and can be used for evaluating multiple drug candidates targeting different human diseases. This multi-functionality increases the model's accuracy and applicability without proportionally increasing complexity.
2Reliability
If endogenous animal genes are replaced with human genes, then the accuracy of human disease modeling is improved, but the complexity of genetic manipulation increases
Solution Approach 1:
The patent implements local quality by selectively replacing only specific endogenous animal genes with corresponding human genes at their native loci, rather than replacing all genes. This approach focuses genetic manipulation on critical gene regions where human protein interactions occur, improving disease modeling accuracy while limiting the overall complexity of genetic modification.
Solution Approach 2:
The patent uses preliminary action by first identifying and selecting the specific human genes and their interaction networks that are critical for the target human disease, then designing targeted gene replacement strategies. This preliminary planning allows for precise genetic manipulation that achieves high modeling accuracy without unnecessary complexity.
3Measurement precision
If multiple human genes are introduced to express interacting proteins, then the accuracy of drug evaluation is improved, but the time and resources required for model development increase
Solution Approach 1:
The patent applies segmentation by dividing the development process into distinct stages: first identifying critical human protein interaction networks, then selecting specific genes for introduction, followed by targeted gene replacement, and finally validation. This segmented approach allows systematic progression that reduces overall development time while maintaining high accuracy in drug evaluation capability.
Solution Approach 2:
The patent uses copying by introducing human genes that encode proteins with known interaction patterns from human biology into the animal model. By copying these established human protein-protein interaction networks into the transgenic animal, the model rapidly achieves high fidelity for drug evaluation without requiring extensive de novo characterization of each interaction.
Data Source
AI summary
This present invention relates to transgenic animals useful to study human diseases. Specifically, the invention relates to transgenic animals expressing at least two human proteins (optionally in replacement of the counterpart proteins in the animal) whereas a first human protein interacts with a second human protein. The transgenic animals can then be used for evaluating drugs or building disease models that are related to the expressed human proteins in the animals. The animals and methods disclosed herein reduce the possibility identifying a false-positive compound—the compound that show an effect in a naturally-occurring, non-transgenic animal but may not necessarily work or be therapeutic in human, since the compound may only interrupt the interaction between two animal proteins not necessarily two related human proteins. Also, the animals and methods disclosed herein reduce the possibility of identifying a false-negative compound—a compound that does not work or have any effect in a naturally-occurring, non-transgenic animal but may have therapeutic effect in human, since the compound may only interrupt the interaction between at least two relevant human proteins not necessarily two related animal proteins.