Humanized TMPRSS Rodent Model for Human-Specific Antiviral Testing
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for an in vivo system to identify and test compounds targeting human type II transmembrane serine proteases for the treatment and prevention of viral infections, as existing models are inadequate.
Innovation Solution
Genetically modify rodents to include humanized Tmprss genes, specifically encoding human TMPRSS proteins with high sequence identity to their rodent counterparts, to create an in vivo model for testing therapeutic compounds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If rodent models with endogenous Tmprss genes are used, then the model is simple and easy to maintain, but it cannot effectively test therapeutics targeting human TMPRSS proteins due to species differences
Solution Approach 1:
The invention applies local quality by replacing only the ectodomain region of the rodent Tmprss gene with the corresponding human TMPRSS sequence, while retaining the rodent's native promoter, transmembrane domain, and cytoplasmic tail. This targeted regional substitution allows the protein to have human-specific functional properties in the ectodomain (enabling therapeutic testing) while maintaining rodent cellular context and simplifying model maintenance.
Solution Approach 2:
The Tmprss gene is segmented into functional domains: the ectodomain (replaced with human sequence for therapeutic relevance) and the transmembrane/cytoplasmic portions (retained as rodent sequence for model simplicity). This segmentation allows selective humanization of only the region necessary for therapeutic interaction while preserving rodent model advantages.
2Reliability
If humanized Tmprss gene is introduced into rodent genome, then the model can test human-specific compounds, but the genetic engineering process becomes more complex
Solution Approach 1:
Instead of complete humanization which would be extremely complex, the invention humanizes only the ectodomain region that directly interacts with viral substrates and therapeutic compounds. This localized approach achieves the necessary reliability for human therapeutic testing while significantly reducing genetic engineering complexity compared to full gene replacement.
Solution Approach 2:
The rodent Tmprss gene structure serves as an intermediary framework that accepts the human ectodomain sequence. This hybrid construction allows the model to bridge human-specific therapeutic interactions with rodent model simplicity, achieving reliable therapeutic testing without requiring complete human genome introduction.
3Reliability
If complete human TMPRSS gene is used, then human protein function is perfectly replicated, but the model loses rodent physiological context
Solution Approach 1:
The invention applies local quality by selectively replacing only the ectodomain with human sequence while maintaining rodent sequences for transmembrane and cytoplasmic regions. This ensures human-specific functional properties where needed (ectodomain for viral interaction) while preserving rodent physiological context (cellular environment, signaling pathways) for model utility.
Solution Approach 2:
The protein is segmented into functional regions with different origins: human ectodomain for specific therapeutic interactions and rodent transmembrane/cytoplasmic portions for physiological context. This segmentation allows the model to maintain both human protein function replication and rodent model versatility simultaneously.
Data Source
Figure 1A
Figure 1B
Figure 1C
AI summary
Genetically modified rodents such as mice and rats, and methods and compositions for making and using the same, are provided. The rodents comprise a humanization of at least one endogenous rodent Tmprss gene, such as an endogenous rodent Tmprss2, Tmprss4, or Tmprss11d gene.