Chimeric Ligand Receptor Control for Conditional Therapeutic Gene Expression
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Solution Overview
Problem
There is a long-felt need for a method to control gene expression in genetically modified cells for the long-term delivery of therapeutic agents.
Innovation Solution
A composition comprising an inducible transgene construct and a receptor construct, integrated into a cell's genomic sequence, where the exogenous receptor, upon ligand binding, transduces an intracellular signal to modify gene expression, allowing conditional gene expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If constitutive expression is used to deliver therapeutic agents, then continuous supply is achieved, but uncontrolled expression causes toxicity and immune responses
Solution Approach 1:
The patent implements dynamic control of gene expression by replacing constitutive promoters with inducible promoters that respond to external signals. The system transitions from static continuous expression to dynamic conditional expression, allowing therapeutic agents to be produced only when needed, thereby maintaining continuous supply capability while eliminating uncontrolled expression toxicity.
Solution Approach 2:
The patent changes the operational parameters of gene expression by using inducible promoters that can be activated or deactivated by external inducers. This allows precise control over when and how much therapeutic agent is produced, transforming the expression pattern from continuous to conditional, thus resolving the toxicity issue while preserving continuous supply capability.
2Object-affected harmful factors
If inducible systems are used to control gene expression, then toxicity is reduced, but long-term stable expression is compromised
Solution Approach 1:
The patent introduces an intermediary component - the inducible promoter system - that mediates between the therapeutic gene and the cell's transcriptional machinery. This intermediary allows controlled activation of gene expression only when the appropriate inducer is present, reducing toxicity while enabling long-term stable expression through reversible induction rather than permanent modification.
Solution Approach 2:
The patent implements periodic action by using inducible promoters that can be activated in cycles. The therapeutic gene is expressed only during periods when the inducer is present, and remains silent when the inducer is absent. This periodic expression pattern reduces cumulative toxicity while maintaining the capability for long-term stable expression over extended periods.
3Measurement precision
If multiple components are integrated into control system, then precision is improved, but system complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the gene expression control system into distinct functional modules: the therapeutic gene, the inducible promoter, and the response element. Each component has a specific function, and they work together in a modular fashion. This segmentation improves control precision while managing complexity through functional decomposition rather than creating a monolithic complex system.
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
Enables controlled and reversible or irreversible modification of gene expression in various cell types, including prokaryotic and eukaryotic cells, for therapeutic applications.
Implementation Method 1
the exogenous reporter, upon binding a ligand, transduces an intracellular signal that targets the inducible promoter of (a) to modify gene expression
Data Source
AI summary
Disclosed are composition comprising (a) an inducible transgene construct, comprising a sequence encoding an inducible promoter and a sequence encoding a transgene, and (b) a receptor construct, comprising a sequence encoding a constitutive promoter and a sequence encoding an exogenous receptor, wherein, upon integration of the construct of (a) and the construct of (b) into a genomic sequence of a cell, the exogenous reporter is expressed, and wherein the exogenous reporter, upon binding a ligand, transduces an intracellular signal that targets the inducible promoter of (a) to modify gene expression. Methods for introducing compositions into cells and the use of the resultant cells in adoptive cell therapies are also provided.