Humanized TTR Locus Non-Human Animal Models for Amyloidosis
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Solution Overview
Problem
Current methods lack suitable non-human animal models that accurately mimic human transthyretin (TTR) amyloidosis, hindering the testing of therapeutic agents and pharmacokinetic/pharmacodynamic studies, as they do not provide a true human target or close approximation of human-TTR-targeting reagents.
Innovation Solution
Development of non-human animals with a humanized TTR locus, where the endogenous Ttr locus is genetically modified to include a human TTR sequence, allowing for the expression of human transthyretin protein, enabling the assessment and optimization of human-TTR-targeting reagents in vivo.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-human animals with endogenous Ttr locus are used, then the animal model is simple and easy to maintain, but it cannot accurately mimic human TTR amyloidosis and provide true human target for testing
Solution Approach 1:
The patent applies copying by replacing the endogenous mouse Ttr locus with a humanized Ttr locus that contains the human TTR coding sequence. This creates a genetic copy of the human gene in the mouse model, enabling the animal to produce human TTR protein and accurately mimic human TTR amyloidosis pathology, thereby providing a true human target for testing therapeutic reagents.
Solution Approach 2:
The patent applies local quality by making selective replacement of specific regions of the Ttr locus. The coding sequence is replaced with human TTR sequence, while regulatory elements like promoters and introns may be retained from the mouse locus. This localized humanization strategy ensures human TTR production while maintaining appropriate expression patterns and regulation.
2Measurement precision
If human TTR sequence is introduced into non-human animal, then human TTR protein can be expressed for accurate target testing, but the animal model becomes more complex
Solution Approach 1:
The patent introduces a human TTR coding sequence into the mouse Ttr locus, creating a genetically modified animal that expresses human TTR protein. This enables precise testing of human-TTR-targeting reagents in vivo, as the humanized protein and gene are the only version of TTR present, providing accurate pharmacokinetic and pharmacodynamic data.
Solution Approach 2:
The patent uses the mouse Ttr locus as an intermediary platform to express human TTR. The mouse promoter and regulatory elements serve as intermediaries that control human TTR expression in the appropriate tissue contexts, enabling accurate modeling of human disease while utilizing the mouse system for experimental purposes.
3Productivity
If existing animal models are used without humanized TTR locus, then the model system is well-established and easy to work with, but therapeutic agents cannot be properly tested for efficacy and mode of action
Solution Approach 1:
The patent applies preliminary action by pre-establishing the humanized Ttr locus in the animal model before conducting therapeutic testing. The human TTR gene is integrated into the mouse genome in advance, creating a stable transgenic line that can be used for subsequent pharmacokinetic, pharmacodynamic, and efficacy studies of human-TTR-targeting reagents.
Solution Approach 2:
The patent creates a universal mouse model system that serves multiple functions: it models human TTR amyloidosis pathology, expresses human TTR protein for targeted reagent testing, and provides a platform for both preclinical efficacy studies and mechanistic investigations. This multi-functional model replaces the need for multiple separate systems.
Data Source
AI summary
Non-human animal genomes, non-human animal cells, and non-human animals comprising a humanized TTR locus and methods of using such non-human animal genomes, non-human animal cells, and non-human animals are provided. Non-human animal cells or non-human animals comprising a humanized TTR locus express a human transthyretin protein or a chimeric transthyretin protein, fragments of which are from human transthyretin. Methods are provided for using such non-human animals comprising a humanized TTR locus to assess in vivo efficacy of human-TTR-targeting reagents such as nuclease agents designed to target human TTR. Methods are also provided for making such non-human animals comprising a humanized TTR locus.