TREMs Modulate tRNA Pools for Mutant Codon Translation
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Solution Overview
Problem
Current methods lack effective modulation of tRNA pools in cells to treat or prevent diseases, as they fail to accurately target and adjust the relative amounts of tRNA moieties that pair with specific codons, leading to compromised protein production and function due to SNPs and other genetic variations.
Innovation Solution
The use of tRNA-based effector molecules (TREMs) that pair with specific codons to modulate the tRNA pool by increasing the abundance of isoacceptor tRNAs that correspond to mutant codons, thereby improving protein translation and function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If conventional methods are used to modulate tRNA pools, then general tRNA levels may be increased, but specific tRNA moieties that pair with mutant codons cannot be accurately targeted or adjusted
Solution Approach 1:
The patent applies local quality by designing TREMs with anticodons specifically matched to mutant codons (e.g.,anticodon 3'‑CCA-5' for codon 5'‑UGG-3'). This enables selective modulation of specific tRNA moieties (e.g., tRNA-Trp) that pair with particular mutant codons, rather than non-specifically increasing all tRNA levels. The specificity is achieved through precise anticodon-codon pairing at the local molecular interaction level.
Solution Approach 2:
The patent employs parameter changes by modifying the anticodon sequence of TREMs to match specific mutant codons. By changing the anticodon parameter (nucleotide sequence), the TREMs can selectively bind to and modulate specific tRNA moieties corresponding to mutant codons. This allows precise control over which tRNA species are upregulated, addressing the need for specificity in tRNA pool modulation.
2Productivity
If TREMs are designed to pair with specific codons, then translation efficiency for those codons improves, but the complexity of designing and selecting appropriate TREMs increases
Solution Approach 1:
The patent applies universality by using a standardized TREM platform that can be adapted to target any codon-anticodon pair. The core TREM structure and delivery mechanism remain universal, while only the anticodon sequence needs to be customized for each specific mutant codon. This multi-functional approach allows the same platform to address various different codon usage issues across different genes and diseases.
Solution Approach 2:
The patent employs preliminary action by providing a catalog or library of pre-designed TREMs with anticodons matched to common mutant codons. This allows researchers to select appropriate TREMs based on their specific mutant codon without having to design from scratch, thereby reducing the complexity and time required for TREM development while maintaining high translation efficiency.
3Stability of the object's composition
If the abundance of isoacceptor tRNAs is increased to match mutant codons, then protein expression stability improves, but the difficulty of detecting and measuring specific tRNA moiety levels increases
Solution Approach 1:
The patent applies the intermediary principle by using TREMs as mediator molecules that can be detected and quantified. The TREMs serve as a measurable proxy for the abundance of specific tRNA moieties, as their levels directly reflect the success of isoacceptor tRNA upregulation. This intermediary approach simplifies measurement compared to directly detecting endogenous tRNA species.
Solution Approach 2:
The patent employs feedback by establishing methods to measure tRNA pool composition and use this information to guide further TREM administration. By monitoring changes in specific tRNA moiety levels and protein expression outcomes, the dosage and timing of TREM treatment can be adjusted to optimize protein expression stability while maintaining appropriate tRNA abundances.
Data Source
AI summary
The invention relates generally to uses of tRNA-based effector molecules (TREMs) and methods of making the same.