Cxcl10-Deficient Mouse Model for Low-Grade Glioma Xenografts
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Solution Overview
Problem
Current models for low-grade glioma (LGG) in mice are limited by premature senescence and dependence on a supportive immune environment, hindering the development of effective therapeutic strategies for pediatric brain tumors.
Innovation Solution
The development of a humanized mouse model using CRISPR/Cas9-engineered human induced pluripotent stem cells (hiPSCs) to generate LGGs, specifically silencing Cxcl10 expression, allowing for the long-term growth of patient-derived and hiPSC-derived LGGs in vivo, and identifying the CD4+ T cell-astrocyte Cxcl10 axis crucial for xenograft formation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If current mouse models for low-grade glioma are used, then the models can be established quickly, but the models suffer from premature senescence and dependence on supportive immune environment, limiting their utility for long-term therapeutic testing
Solution Approach 1:
The patent modifies the immune environment parameter by engineering mice with depleted CD4+ T cells and reduced astrocyte Cxcl10 expression. This parameter change creates an immunodeficient state that allows LGG xenografts to grow long-term without premature senescence, resolving the contradiction between model duration and reliability
Solution Approach 2:
The patent introduces Cxcl10 as an intermediary molecule whose expression is specifically reduced in the engineered mouse model. This intermediary mediates the interaction between the immune environment and tumor growth, allowing long-term xenograft survival by blocking the Cxcl10-dependent suppression mechanism
2Duration of action of stationary object
If patient-derived xenografts are implanted in wild-type mice, then the immune environment provides initial support, but the tumors undergo premature senescence and cannot be maintained long-term for therapeutic testing
Solution Approach 1:
The patent changes the immune environment parameter by depleting CD4+ T cells and reducing Cxcl10 expression in astrocytes. This creates a permissive environment that maintains xenografts long-term without the harmful immune responses that cause premature senescence in wild-type mice
Solution Approach 2:
The patent performs preliminary engineering of the mouse model before xenograft implantation, creating the immunodeficient state with depleted CD4+ T cells and reduced Cxcl10 expression. This preliminary action ensures the environment is prepared to support long-term tumor growth from the moment of implantation
Data Source
AI summary
Among the various aspects of the present disclosure is the provision of engineered cells, animal models, and uses thereof for modeling low grade glioma (LGG). An aspect of the present disclosure provides for a population of cells engineered to silence, downregulate, knock out, or reduce or knock down Cxcl10 expression. Another aspect of the present disclosure provides for an animal engineered to be deficient in Cxcl10, downregulate or reduce expression of Cxcl10, knock out Cxcl10, or knock down Cxcl10 (e.g., Cxcl10â/â mice). Yet another aspect of the present disclosure provides for a method of growing tumor cell lines or patient-derived xenografts for LGG tumors in an animal (e.g., mouse, rat) including providing a mouse or rat harboring somatic homozygous deletion in the Rag1 or Cxcl10 gene, and implanting an amount of the cells in mice sufficient to grow a tumor.