Codon Optimization Method for mRNA Therapeutics
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Solution Overview
Problem
Current methods for codon optimization in mRNA therapy often result in reduced functional activity of encoded proteins due to the removal of important translation control information and improper folding, and they either use only one codon per amino acid or fail to account for tRNA abundance, leading to inefficient protein translation and yield.
Innovation Solution
A computer-implemented method that generates optimized nucleotide sequences by selecting codons based on their usage frequency, distributing removed codon usage frequencies among remaining codons, and filtering sequences to ensure they meet criteria such as avoiding termination signals and maintaining appropriate guanine-cytosine content and codon adaptation index, thereby improving protein expression without altering the amino acid sequence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If every codon is replaced with the most frequently used codon for each amino acid (one-to-one sequence), then codon optimization is simplified and computational efficiency is improved, but the sequence loses important translation control information and results in reduced functional activity of the encoded protein
Solution Approach 1:
The patent applies local quality by differentiating between two types of codon positions: (1) positions where codon selection should favor high-frequency codons to optimize translation efficiency, and (2) positions where rare codons should be preserved because they contain important regulatory information for translation control and protein folding. This local differentiation resolves the contradiction by allowing computational efficiency in most positions while preserving functional integrity in critical positions.
Solution Approach 2:
The patent changes the parameter of codon selection from a binary choice (most frequent vs. any) to a multi-parameter decision process that considers: (a) codon usage frequency, (b) local sequence context, (c) tRNA abundance, and (d) functional importance of translation control. This multi-parameter approach allows the system to maintain high computational efficiency while preserving essential regulatory information.
2Ease of manufacture
If rare codons are removed from the sequence to simplify optimization, then the sequence becomes easier to synthesize and more computationally efficient, but tRNA depletion occurs leading to inefficient protein translation and reduced yield
Solution Approach 1:
The patent applies preliminary action by pre-identifying and preserving rare codons at positions where they are functionally important before the codon optimization process begins. This pre-screening ensures that subsequent optimization steps do not remove these critical rare codons, thereby preventing tRNA depletion and maintaining efficient protein translation while still allowing simplification in non-critical regions.
3Productivity
If codon optimization is performed to increase protein expression, then translation efficiency is improved, but the sequence may acquire termination signals or improper folding elements that reduce protein yield
Solution Approach 1:
The patent applies preliminary anti-action by proactively screening the optimized sequence for harmful elements such as premature termination signals, secondary structure elements that could cause misfolding, and other detrimental motifs before the sequence is synthesized and expressed. This pre-screening and removal of harmful elements prevents reduction in protein yield while maintaining the benefits of codon optimization.
Data Source
AI summary
A method for generated an optimized nucleotide sequence is provided. The method comprises at least normalizing a codon usage table and selection of codons for a given amino acid sequence based on the usage frequency of the codons in the normalized codon usage table. The method may comprise generating a list of a plurality of optimized nucleotide sequences encoding the amino acid sequence, filtering the list of optimized nucleotide sequences, synthesizing one or more optimized nucleotide sequence, and/or administering one or more synthesized optimized nucleotide sequence.