Codon Optimality Modulation for mRNA Stability Control
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Solution Overview
Problem
Current methods for regulating mRNA stability and protein expression in cells are inadequate, as existing sequence and structural elements in untranslated regions cannot account for the wide variation in mRNA half-lives across the transcriptome, suggesting the need for additional features that modulate transcript stability.
Innovation Solution
Modifying codon optimality in nucleic acid sequences by replacing optimal or non-optimal codons with synonymous codons to alter mRNA stability and protein expression levels, with specific optimal and non-optimal codons identified to achieve significant changes in protein expression levels up to 100% difference compared to wild-type sequences.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If existing sequence and structural elements in untranslated regions are used to regulate mRNA stability, then some control over gene expression is achieved, but the wide variation in mRNA half-lives across the transcriptome cannot be adequately explained
Solution Approach 1:
The patent changes the parameter of codon optimality in the coding sequence to regulate mRNA stability. By substituting optimal codons with non-optimal codons (or vice versa) while maintaining the same amino acid sequence, the invention demonstrates that codon composition directly influences mRNA half-life, thereby explaining the unaccounted variation in mRNA stability across the transcriptome
2Productivity
If optimal codons are used in nucleic acid sequences, then translational efficiency is improved, but mRNA stability decreases leading to shorter half-lives
Solution Approach 1:
The patent systematically varies the parameter of codon optimality to demonstrate its dual effect on translation and stability. By creating nucleic acid sequences with different proportions of optimal versus non-optimal codons encoding the same protein, the invention shows that high optimal codon content increases translational efficiency but decreases mRNA half-life, while the opposite pattern reverses these effects
3Duration of action of stationary object
If non-optimal codons are used in nucleic acid sequences, then mRNA stability is improved leading to longer half-lives, but translational efficiency decreases
Solution Approach 1:
The patent manipulates the codon composition parameter by substituting non-optimal codons for optimal ones in the coding sequence. This parameter change results in increased mRNA stability and extended half-life, while simultaneously reducing translational efficiency, thereby demonstrating the trade-off between these two critical parameters of gene expression
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
This approach allows for predictable modulation of mRNA stability and protein expression levels without altering the amino acid sequence, demonstrating a direct correlation between codon optimality and mRNA stability, and translational efficiency, thereby enhancing protein production and therapeutic applications.
Implementation Method 1
Modifying codon optimality in nucleic acid sequences by replacing optimal or non-optimal codons with synonymous codons to alter mRNA stability and protein expression levels
Data Source
AI summary
A synthetic nucleic acid which encodes a protein wherein at least one optimal or non-optimal codon in a wild type nucleic acid encoding the protein has been replaced respectively with one or more non-optimal codons or optimal codons encoding the same amino acid.