RNA Therapeutics Codon Optimization for Stability and Translation
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Solution Overview
Problem
Current RNA-based therapeutic methods face challenges such as RNA instability due to degradation, integration into host genomic DNA, and inefficient protein expression, particularly in primary cells, leading to potential damage and reduced efficacy.
Innovation Solution
The method involves altering the codon sequence of RNA therapeutic molecules to increase GC content, substituting nucleotides with analogs like pseudouridine, and encapsulating them in structures like lipid nanoparticles to enhance stability and translation, while maintaining structural integrity through secondary structure optimization.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If DNA is introduced into host cells for protein expression, then protein production can be achieved, but DNA may integrate into host genomic DNA causing alterations and damage
Solution Approach 1:
The patent uses RNA as an intermediary molecule to transmit genetic information from DNA to protein without requiring the foreign DNA to remain in the host cell. The RNA is transient and degrades naturally after translation, avoiding permanent genomic integration and associated hazards while still enabling protein production.
2Productivity
If heterologous DNA is introduced into cells, then protein expression can occur, but the DNA may be inherited by daughter cells or offspring
Solution Approach 1:
The patent employs transient RNA molecules that are inexpensive to produce and designed to be short-lived within the cell. The RNA performs its function of directing protein synthesis and then naturally degrades, avoiding the problem of unintended inheritance by daughter cells that would occur with stable DNA integration.
3Productivity
If multiple processing steps are used from DNA to protein, then protein can be produced, but lag times and opportunities for error and damage increase
Solution Approach 1:
The patent performs preliminary action by synthesizing the RNA molecule outside the cell with all necessary processing already complete (cap structure, poly-A tail, coding sequence). This pre-processed RNA is then directly introduced into the cell for translation, eliminating the time-consuming steps of nuclear transcription and processing that would occur if DNA were introduced instead.
4Productivity
If RNA is used as a therapeutic agent, then direct protein expression can be achieved, but RNA is unstable and highly susceptible to degradation
Solution Approach 1:
The patent applies parameter changes by chemically modifying the RNA molecule's structure through various means including modified nucleotides (such as pseudouridine), altered phosphodiester bonds, and optimized sequence composition. These parameter changes maintain the RNA's ability to direct protein synthesis while significantly enhancing its resistance to degradation by nucleases and improving overall molecular stability.
5Productivity
If codon sequence is altered to increase GC content, then RNA stability and translation efficiency can be improved, but the original sequence information must be preserved
Solution Approach 1:
The patent applies local quality by making targeted, localized changes to specific codons within the RNA sequence rather than altering the entire sequence. Each codon is individually optimized for increased GC content and improved translation efficiency while maintaining the same amino acid encoding, thus preserving the original protein sequence information while enhancing RNA performance at specific locations.
Data Source
AI summary
Embodiments herein describe systems and methods to enhance RNA stability and uses thereof. Many embodiments alter the sequence of an RNA therapeutic molecule (e.g., vaccines) to encode for a variant peptide while maintaining and/or increasing stability of the RNA therapeutic.