Transgenic Mouse Expressing Human Cereblon for Drug Interaction Studies

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Solution Overview

Problem

Current animal models, such as mice, are inadequate for studying the interaction between cereblon (CRBN) and cereblon E3 ubiquitin ligase modulating compounds (CMCs) due to the inability of mouse CRBN to properly engage with these compounds, limiting the understanding of drug efficacy, toxicity, and mechanism of action.

Innovation Solution

Development of transgenic mice expressing human CRBN, allowing for the study of CRBN interactions with CMCs and enabling the evaluation of drug efficacy, toxicity, and mechanism of action, as well as optimization of dosing regimens and combination therapies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If transgenic mice expressing human CRBN are developed, then the ability to study CRBN-CMC interactions is improved, but the device complexity and manufacturing difficulty increase

Engineering Contradiction:

Improveability to study CRBN-CMC interactionsVSAvoidtransgenic mouse model complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent changes the species parameter of the CRBN protein from mouse to human in the transgenic mouse model. This parameter change enables the mouse model to properly interact with human CMCs, resolving the fundamental incompatibility issue while maintaining the advantages of using mouse models for drug studies.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If transgenic mice expressing human CRBN are developed, then drug efficacy evaluation capability is improved, but the ease of manufacture and operation deteriorates

Engineering Contradiction:

Improvedrug efficacy evaluation capabilityVSAvoidease of conducting drug studies

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent creates a copy of the human CRBN protein in the transgenic mouse model. This copied human protein allows researchers to study human CMC interactions in an in vivo system, combining the advantages of human protein specificity with the practical benefits of mouse model ease of use.

Inventive Principle:

Principle #26Copying

3Loss of information

If transgenic mice expressing human CRBN are developed, then understanding of drug mechanism of action is improved, but the loss of time and resources increases

Engineering Contradiction:

Improveunderstanding of drug mechanism of actionVSAvoidtime for model development and validation

Core Design Contradiction:

Loss of informationVSLoss of time

Solution Approach 1:

The patent performs preliminary action by developing the transgenic mouse model with human CRBN expression in advance. This pre-established model provides a ready-to-use platform for studying CRBN-CMC interactions, eliminating the need to develop new models for each study and reducing overall research time and resource investment.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS20240389562A1Transgenic mouse expressing human cereblon

Publication Date: 2024.11.28 CELGENE CORP

AI summary

Provided are transgenic mice whose genome comprises a nucleic acid sequence encoding human cereblon (CRBN) or a fragment thereof, wherein endogenous mouse CRBN is not expressed in the transgenic mice. Also provided are cells, cell lines, tissues, and organs derivable from the transgenic mice, and methods for producing and using such mice.