Inducible Caspase-9 Cell Ablation for Replacement Organ Models
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Solution Overview
Problem
Existing inducible cell death systems, such as those using diphtheria toxin, are not suitable for human cells due to toxicity, and there is a need for a method that can efficiently and rapidly induce target cell death without affecting non-target human cells.
Innovation Solution
A non-human animal model with a system incorporating a cell-specific promoter and an exogenous caspase 9 gene, which can be induced by a chemical dimerizer, optionally combined with a site-specific recombinase and apoptosis-promoting agents, to selectively kill target cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If diphtheria toxin is used as an inducer to achieve inducible cell death in non-dividing cells, then target cell death is effectively induced, but non-target human cells are damaged due to toxicity
Solution Approach 1:
The patent introduces a receptor protein as an intermediary component that selectively binds the inducer molecule. This receptor acts as a mediator between the inducer and target cells, enabling specific cell death only in cells expressing the receptor while leaving non-target human cells unaffected. The receptor serves as a selective gateway that prevents the inducer from damaging non-target cells.
Solution Approach 2:
The patent applies local quality by creating cell-type specificity through the receptor protein expression pattern. The inducer system is designed to have different effects in different cell types based on whether they express the receptor protein. Target cells with the receptor undergo cell death, while non-target cells without the receptor remain unaffected, achieving localized harmful effect only where needed.
2Reliability
If HSV-TK system is used for inducible cell death, then target cell death can be controlled, but the system cannot be applied to non-dividing cells and has immunogenicity
Solution Approach 1:
The patent changes the fundamental mechanism from DNA-based (HSV-TK requiring cell division for gene expression) to protein-based (receptor-mediated toxin binding). This parameter change in the underlying biological mechanism allows the system to function in non-dividing cells, as protein expression and binding do not require cell division, thereby expanding adaptability while maintaining controllable cell death.
3Productivity
If diphtheria toxin is used to achieve high-efficiency target cell removal, then rapid cell death is induced, but the toxicity damages non-target human cells
Solution Approach 1:
The receptor protein serves as a selective intermediary that allows high-efficiency target cell removal while protecting non-target cells. The inducer binds specifically to the receptor, creating a targeted delivery mechanism that maintains high productivity in killing target cells while the receptor's selective expression prevents toxicity from affecting non-target human cells.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The system allows for high-efficiency, rapid induction of target cell death in non-human animals without affecting non-target human cells, enabling the production of replacement organs using human progenitor cells.
Implementation Method 1
an exogenous caspase 9 gene in which expression is inducible downstream of the cell-specific promoter
Implementation Method 2
a chemical inducer of dimerization
Data Source
Figure 1(A)~1(B)
Figure 2
Figure 3
AI summary
A non-human animal including a system configured to kill a target cell in vivo, in which the target cell includes a chromosome having a cell-specific promoter and an exogenous caspase 9 gene in which expression is inducible downstream of the cell-specific promoter, or a chromosome having a high-expression promoter and an exogenous caspase 9 gene in which expression is inducible downstream of the high-expression promoter.