Nucleic Acid Modified Cell for Temporal Gene Expression Control
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Solution Overview
Problem
Current CAR T cell therapies face challenges such as primary resistance, relapse, and toxicities like cytokine release syndrome and immune effector cell associated neurotoxicity syndrome, due to heterogeneity and resistance mechanisms in infused T cells.
Innovation Solution
A nucleic acid modified biological cell is developed, comprising a first expressible nucleotide sequence encoding a target, a recombinant nucleic acid sequence to modulate the expression of the first sequence, and a third nucleotide sequence outside the genome to inhibit the second sequence, allowing for temporal control of target gene expression during cell expansion phases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are engineered to proliferate and eliminate targeted cells, then therapeutic efficacy is improved, but toxicities such as cytokine release syndrome and immune effector cell associated neurotoxicity syndrome increase
Solution Approach 1:
The patent introduces a preliminary control mechanism by integrating a modulatory nucleic acid sequence that can preemptively regulate target gene expression. The sequence is designed to be activated or deactivated at specific time points before toxicities manifest, allowing prevention rather than treatment. This is achieved through the incorporation of regulatory elements that respond to cellular states or external triggers to modulate proliferation and cytokine production in advance.
Solution Approach 2:
The patent employs parameter changes by modifying the expression levels of target genes at different time points during CAR T cell therapy. The modulatory nucleic acid sequence enables dynamic adjustment of gene expression parameters, such as proliferation rate and cytokine production, to optimize therapeutic efficacy while minimizing toxicities. This temporal control allows the system to adapt expression levels to match therapeutic needs at each stage.
2Productivity
If T cell clones are engineered for strong proliferation and target elimination, then therapeutic effect is enhanced, but persistence and fitness are reduced due to exhaustion
Solution Approach 1:
The patent implements periodic action through the modulatory nucleic acid sequence that enables cyclic or phased expression of target genes. Instead of continuous high-level expression, the system alternates between high expression (for target elimination) and low expression (for recovery and persistence). This periodic modulation allows CAR T cells to maintain fitness while delivering therapeutic effects in waves, preventing exhaustion.
Solution Approach 2:
The patent applies dynamics by creating a dynamic expression system where target gene levels can change over time in response to cellular needs and environmental cues. The modulatory nucleic acid sequence introduces flexibility, allowing the system to transition between different expression states rather than being locked in a fixed high-expression mode. This dynamic adaptation preserves T cell functionality and persistence.
3Ease of operation
If modulatory nucleic acid sequences are integrated into the genome, then temporal control of gene expression is achieved, but device complexity increases
Solution Approach 1:
The patent uses an intermediary approach by introducing a modulatory nucleic acid sequence that acts as a mediator between the target gene and the cellular machinery. This intermediary sequence contains regulatory elements that respond to specific signals or conditions to control target gene expression. Rather than directly engineering complex control circuits, the system uses this intermediary to translate simple triggers into regulated expression patterns.
Solution Approach 2:
The patent applies universality by designing a modulatory nucleic acid sequence that can be applied to multiple different target genes and CAR T cell contexts. The regulatory elements in the sequence are engineered to work with various promoters and gene targets, making the solution broadly applicable. This multi-functionality reduces the need for custom-designed complex control systems for each specific application.
Data Source
AI summary
The present invention relates to a nucleic acid modified biological cell and a method for modulating, in a nucleic acid modified cell, the expression of a nucleotide sequence encoding a target.