Humanized Cxcl13 Gene Rodent Model for Human Cell Engraftment
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Solution Overview
Problem
Current non-human animal models used for studying human cell engraftment and disease pathogenesis do not adequately support the survival and proliferation of human cells, limiting their effectiveness in therapeutic development and cancer research.
Innovation Solution
Genetically modified rodents with a humanized Cxcl13 gene, which includes a rodent Cxcl13 nucleic acid sequence and a human CXCL13 nucleic acid sequence, are developed to enhance the engraftment and proliferation of human cells, such as chronic lymphocytic leukemic cells, by encoding a humanized Cxcl13 polypeptide with a chemokine IL-8 like domain identical to the human CXCL13 protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional non-human animal models are used, then the model simplicity and ease of operation are maintained, but the engraftment and proliferation of human cells are insufficient
Solution Approach 1:
The patent applies local quality by humanizing only the Cxcl13 gene in the rodent genome while leaving other genes unchanged. This targeted approach replaces specific rodent Cxcl13 sequences with human CXCL13 sequences to create a localized humanized region that specifically improves human cell engraftment without requiring complete genome replacement, thus balancing reliability improvement with manageable complexity
Solution Approach 2:
The patent changes the genetic parameter of the Cxcl13 gene from rodent to human origin. By modifying the nucleic acid sequence of the Cxcl13 gene to encode human CXCL13 protein while maintaining rodent genome architecture, the patent alters a specific genetic parameter to improve human cell compatibility, achieving better engraftment without overwhelming system complexity
2Reliability
If the entire rodent genome is replaced with human genome, then human cell compatibility is maximized, but the complexity and difficulty of manufacture become unmanageable
Solution Approach 1:
The patent extracts only the essential Cxcl13 gene sequences from the human genome and inserts them into the rodent genome, rather than replacing the entire rodent genome with human genome. This extraction approach isolates the specific genetic element (Cxcl13) that is critical for human cell compatibility, making the manufacturing process feasible while maintaining maximum human cell compatibility where needed
Solution Approach 2:
The patent segments the genome replacement task by focusing solely on the Cxcl13 gene rather than attempting to replace the entire genome. By dividing the complex genome replacement problem into a manageable segment (the Cxcl13 gene), the patent makes the manufacturing process practicable while achieving the critical function of human cell compatibility
Data Source
AI summary
Disclosed herein are rodents (such as, but not limited to, mice and rats) genetically modified to comprise a humanized Cxcl13 gene. The rodents disclosed herein have been shown to support better engraftment and proliferation of human cells such as chronic lymphocytic leukemic cells. Compositions and methods for making such genetically modified rodents, as well as methods of using such genetically modified rodents for testing candidate therapeutic agents (e.g., candidate anti-cancer drugs), are provided.