Modified mRNA for Membrane Protein Expression
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Solution Overview
Problem
Current methodologies for protein expression using DNA face challenges such as integration into host cell genomic DNA, low translation rates, immunogenicity, and difficulties in obtaining effective expression, particularly in primary cells, leading to inefficiencies and errors in protein production.
Innovation Solution
Development of modified mRNA (mmRNA) molecules with structural and chemical features that optimize formulation and delivery, enhance expression rates, improve protein localization, and minimize immune responses and degradation, allowing for efficient intracellular translation and protein production.
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 cell genomic DNA causing alterations and damage
Solution Approach 1:
The patent extracts the protein production function from DNA-based expression systems and transfers it to mRNA-based systems. By using mRNA directly as the expression vehicle instead of DNA, the system achieves protein production without the risk of genomic integration and damage, effectively separating the useful function from the harmful potential
Solution Approach 2:
The patent introduces mRNA as an intermediary molecule between the genetic information and protein production. This intermediary approach allows protein expression without requiring DNA integration into the host genome, thus avoiding genomic damage while maintaining the ability to produce proteins efficiently
2Productivity
If DNA is introduced into cells for expression, then protein can be produced, but multiple processing steps create lag times and opportunities for error
Solution Approach 1:
The patent applies preliminary action by pre-transcribing the genetic information into mRNA outside the cell before delivery. This eliminates the time-consuming steps of nuclear transport and transcription that occur with DNA-based systems, allowing the cell to jump directly to the translation step and significantly reducing expression lag time
Solution Approach 2:
The patent extracts the transcription step from the intracellular process by performing it in vitro before delivery. This removes the transcription bottleneck and associated time delays from the protein production pathway, streamlining the process to focus only on translation
3Productivity
If DNA is introduced into primary cells, then protein expression may be achieved, but expression rates are frequently low or insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of nucleosides within the mRNA molecule. Specifically, substituting certain nucleosides with modified versions optimizes the mRNA's stability and translation efficiency in primary cells, thereby significantly improving both expression rates and reliability without requiring DNA integration
4Productivity
If mRNA is used for protein delivery, then translation can occur, but immunogenicity and low translation rates hamper therapeutic development
Solution Approach 1:
The patent applies parameter changes by systematically modifying nucleoside parameters within the mRNA sequence. These chemical modifications reduce the mRNA's immunogenicity while simultaneously enhancing its translation efficiency, thereby resolving both the harmful immune response and the low translation rate issues
Solution Approach 2:
The patent converts the potentially harmful immunogenicity of mRNA into a benefit by using modified nucleosides that reduce immune recognition. This allows the mRNA to evade immune detection while maintaining high translation rates, effectively turning a liability into an advantage for therapeutic applications
Data Source
AI summary
The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides, primary transcripts and mmRNA molecules.