RGMc Knockout Mouse Model for Iron Metabolism Study

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Solution Overview

Problem

Current understanding of the RGMc gene's role in iron metabolism is limited, and there is a need for an animal model to study its function and potential therapeutic modulation in human diseases like juvenile hemochromatosis, which involves iron overload and associated conditions.

Innovation Solution

Generation of transgenic non-human animals with a disrupted RGMc gene using homologous recombination in embryonic stem cells, creating a knockout model that lacks functional RGMc protein, allowing for the study of RGMc/HFE2's role in iron metabolism and as a model for human diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Loss of information

If RGMc gene is disrupted to create knockout animals, then understanding of RGMc function in iron metabolism is improved, but complexity of animal generation process increases

Engineering Contradiction:

Improveunderstanding of RGMc functionVSAvoidcomplexity of animal generation process

Core Design Contradiction:

Loss of informationVSDevice complexity

Solution Approach 1:

The patent applies preliminary action by first disrupting the RGMc gene in embryonic stem cells through homologous recombination before generating the complete knockout animal. This stepwise approach allows for verification of gene disruption at the cellular level before proceeding to animal generation, thereby managing the complexity of the overall process while achieving the goal of understanding RGMc function.

Inventive Principle:

Principle #10Preliminary action

2Reliability

If transgenic animals are generated to model human diseases, then therapeutic assessment capability is improved, but time and resources required for animal generation increase

Engineering Contradiction:

Improvetherapeutic assessment capabilityVSAvoidtime for animal generation

Core Design Contradiction:

ReliabilityVSLoss of time

Solution Approach 1:

The patent creates a copy of the human disease condition in the animal model by disrupting the RGMc gene, which is orthologous to human HFE2. This allows therapeutic assessment in a living system that replicates human juvenile hemochromatosis pathology, providing reliable preclinical data without requiring direct human experimentation, thus balancing time investment with therapeutic assessment capability.

Inventive Principle:

Principle #26Copying

3Manufacturing precision

If gene targeting is performed in embryonic stem cells, then precision of gene disruption is improved, but difficulty of the procedure increases

Engineering Contradiction:

Improveprecision of gene disruptionVSAvoidease of gene targeting procedure

Core Design Contradiction:

Manufacturing precisionVSEase of manufacture

Solution Approach 1:

The patent uses embryonic stem cells as an intermediary system to achieve precise gene disruption through homologous recombination. The stem cells provide a controlled environment where gene targeting can be verified before introduction into the animal genome. This intermediary approach maintains high precision of gene disruption while managing procedural difficulty through standardized stem cell culture and selection methods.

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS8101816B2RGMc modified transgenic animals

Publication Date: 2012.01.24 NOVARTIS AG

AI summary

The invention provides a new reproducible transgenic mouse model for the study of iron accumulation in the body. In particular, the invention concerns the study of iron overload in an RGMc knockout mouse model and its use in drug discovery and research.