Transgenic Mouse Model for Pompe Disease Therapeutic Testing
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Solution Overview
Problem
There is a need for mouse models to study Pompe disease and test agents effective in its treatment, as current methods lack effective models to accurately assess therapeutic interventions for this inherited lysosomal storage disorder.
Innovation Solution
Development of knockout transgenic mice with disrupted alpha-glucosidase genes, incorporating human alpha-glucosidase mutations, to mimic Pompe disease, allowing for the evaluation of therapeutic agents such as pharmacological chaperones like DNJ, which can increase alpha-glucosidase activity and reduce glycogen levels in disease-relevant tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If knockout transgenic mice with disrupted alpha-glucosidase genes are created to model Pompe disease, then the ability to study Pompe disease and test therapeutic agents is improved, but the complexity of generating and maintaining the mouse model is increased
Solution Approach 1:
The mouse model system is segmented into multiple components: knockout mice lacking endogenous GAA, transgenic lines expressing human GAA with specific mutations (P545L, P285R, E262K, E579K), and controlled breeding schemes. This segmentation allows researchers to systematically study different aspects of Pompe disease by combining these components in specific ways, while maintaining manageable complexity through standardized protocols.
Solution Approach 2:
The patent introduces human GAA transgenes as intermediaries to bridge the gap between mouse models and human disease. These transgenic mice express human mutant GAA enzymes, serving as intermediaries that allow therapeutic agents developed for human Pompe disease to be tested in a controlled animal model system, thereby improving reliability while managing complexity through standardized transgenic technology.
2Reliability
If mouse models are developed to test therapeutic agents, then the evaluation of treatment efficacy is improved, but the time required for model development and validation is increased
Solution Approach 1:
The patent performs preliminary actions by pre-establishing knockout mouse lines lacking endogenous GAA and pre-characterizing human GAA mutations known to cause Pompe disease. These preliminary models and data are made available for immediate use in therapeutic testing, eliminating the need for time-consuming model development during each new study while maintaining high reliability through validated methodologies.
Solution Approach 2:
The patent utilizes parameter changes by creating mouse models with controlled variations in GAA enzyme activity through different human mutation combinations. This allows researchers to quickly adjust disease severity and tissue-specific phenotypes to match different stages of human Pompe disease, enabling rapid evaluation of therapeutic agents without time-consuming model re-development.
3Measurement precision
If human alpha-glucosidase mutations are introduced into mouse models, then the accuracy of simulating human Pompe disease is improved, but the difficulty of generating the transgenic mice is increased
Solution Approach 1:
The patent applies copying by introducing human GAA genes with specific mutations (P545L, P285R, E262K, E579K) into mouse genomes, creating transgenic mice that copy key features of human Pompe disease. This copying approach maintains high accuracy in simulating human disease phenotypes while managing generation difficulty through established transgenic technologies and pre-identified mutation sequences.
Solution Approach 2:
The patent implements local quality by introducing specific human GAA mutations at particular locations in the mouse genome, creating tissue-specific or condition-specific disease models. This allows researchers to focus on particular aspects of Pompe disease (e.g., cardiac vs. skeletal muscle involvement) by controlling which mutations are expressed and in which tissues, thereby improving simulation accuracy while managing complexity through targeted genetic modification.
Data Source
AI summary
The present invention provides mouse models for Pompe disease and methods of using the same to test agents that may be effective in the treatment of Pompe disease.