5′-UTR Sequence Design for Efficient mRNA Translation
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Solution Overview
Problem
Current mRNA-based vaccines and therapeutics face challenges such as inefficient translation due to premature degradation, limited cellular uptake, and high production costs, necessitating improved 5′-untranslated regions (UTRs) to enhance translation efficiency and stability.
Innovation Solution
Development of synthetic nucleic acid molecules with optimized 5′-UTRs, characterized by specific nucleotide sequences and structures that minimize secondary formations, reduce uridine content, and include 5′-CAP structures, along with coding regions and poly(A) tails, to improve translation efficiency and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional 5′-UTR sequences are used in mRNA vaccines, then the mRNA structure is simpler and easier to manufacture, but translation efficiency is insufficient and protein yield is low
Solution Approach 1:
The patent optimizes specific parameters of the 5′-UTR sequence including nucleotide composition (reducing uridine content to 10-30%), sequence length (30-100 nucleotides), and secondary structure characteristics (maintaining ΔG between -5 to -15 kcal/mol) to enhance translation efficiency while keeping the structure manageable for manufacturing
Solution Approach 2:
The patent introduces specific local sequence features within the 5′-UTR including optimized Kozak consensus sequences (gccRccAUGG), specific nucleotide motifs, and controlled secondary structure elements at particular positions to create localized functional regions that enhance translation initiation without requiring complex overall structure
2Productivity
If mRNA production scale is increased to meet demand, then more mRNA molecules are produced, but production costs increase and quality control becomes more difficult
Solution Approach 1:
The patent employs disposable, standardized 5′-UTR sequence modules that can be rapidly synthesized and integrated into mRNA production pipelines, reducing the need for complex, expensive manufacturing equipment and processes while maintaining consistent quality through standardized design elements
Solution Approach 2:
The patent optimizes mRNA stability parameters through controlled 5′-UTR design, extending mRNA half-life and functional duration, which reduces the frequency of administration and overall production requirements, thereby lowering total production costs and simplifying quality control
3Quantity of substance
If coding region length is increased to encode more therapeutic peptides, then therapeutic efficacy is improved, but the total mRNA length increases leading to higher production costs and reduced translation efficiency
Solution Approach 1:
The patent optimizes the 5′-UTR sequence parameters to create a more efficient translation initiation system that can drive high-level expression of longer coding regions. By reducing uridine content and optimizing secondary structure, the patent maintains translation efficiency even when coding regions are extended to encode multiple therapeutic peptides or proteins
Data Source
AI summary
Disclosed are a synthetic nucleic acid molecule including 5′-UTR with improved translation efficiency and a vaccine/therapeutic composition including the same, and more particularly, a 5′-UTR polynucleotide that is imparted with improved translation efficiency based on the specific motif thereof, a synthetic nucleic acid molecule including the same and a vaccine/therapeutic composition including the synthetic nucleic acid molecule. The 5′-UTR polynucleotide effectively induces expression of target proteins due to improved translation efficiency thereof and thus is useful for various RNA-based applications, for example, vaccines, in vivo/ex vivo gene therapy, etc.