Humanized NaV1.7 Mouse Model for Pain Research
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Solution Overview
Problem
Current methods for studying human voltage-gated sodium channels, particularly NaV1.7, are hindered by the complexity of their structure and the lethality of global deletion in mice, making it difficult to develop effective treatments for chronic pain disorders.
Innovation Solution
Genetically engineered non-human animals, such as mice, are created to express human NaV1.7 channels or chimeric variants, allowing for in vivo testing of therapeutic agents and the identification of antagonists for pain treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If global deletion of NaV1.7 is performed in mice, then the role of NaV1.7 in pain transmission can be studied, but the mice die shortly after birth due to failure to feed
Solution Approach 1:
The patent applies local quality by creating mice with tissue-specific or cell-type-specific deletion of NaV1.7, rather than global deletion. This allows study of NaV1.7's role in pain transmission in specific tissues (such as dorsal root ganglia or peripheral nerves) while preserving the channel function in other tissues (such as the brain and olfactory system), thereby avoiding lethality while maintaining research validity.
2Device complexity
If in vitro systems are used to study human NaV channels, then the complex structure can be managed, but the biological relevance and ability to test therapeutic agents is limited
Solution Approach 1:
The patent creates living animal models that copy or replicate the complex biological system of human NaV channels in an in vivo context. By generating mice with humanized NaV1.7 channels or specific knockin/knockout models, the patent enables therapeutic agents to be tested in a biologically relevant system that maintains the complexity and functionality of real neural tissue, thereby bridging the gap between simplified in vitro models and complex in vivo biology.
3Adaptability or versatility
If human NaV1.7 channels are expressed in non-human animals, then in vivo testing of therapeutic agents becomes possible, but the animals must be genetically engineered
Solution Approach 1:
The patent applies segmentation by using targeted gene modification techniques such as CRISPR-Cas9, homologous recombination, or transgenic technology to introduce human NaV1.7 channels at specific loci in the animal genome. This allows precise insertion of the human channel gene (or functional equivalent) into the animal model, enabling in vivo therapeutic testing while managing the genetic engineering complexity through established molecular biology methods.
Data Source
AI summary
Genetically modified non-human animals and methods and compositions for making and using them are provided, wherein the genetic modification comprises a humanization of an extracellular loop of an endogenous NaV channel gene, in particular a humanization of the one or more extracellular pore loops of a NaV1.7 channel protein. Genetically modified non-human animals are also provided, wherein the genetic modification comprises replacement of an endogenous NaV channel gene, in particular a replacement of the endogenous NaV1.7 gene with a human NaV1.7 gene, and wherein the genetically modified non-human animals are capable of generating action potentials and communicating through the excitable cells of the genetically modified non-human animals via the expressed human or humanized NaV1.7 protein the surface of the excitable cells. Genetically modified mice are described, including mice that express the human or humanized NaV1.7 gene from the endogenous NaV1.7 locus, and wherein the mice comprise functional β-subunits.