Lariat-Cap mRNA Structure for Intracellular Stability
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Solution Overview
Problem
mRNA has lower structural stability than DNA, leading to challenges in industrial use, particularly in mRNA vaccines where high doses are required due to short half-life, causing instability and potential side effects.
Innovation Solution
A lariat-cap structure is introduced at the 5' end of mRNA using ribozymes, enhancing stability and biosynthesis by forming a lariat-cap structure through in vitro transcription, which includes sequences from Didymium iridis, Allovahlkampfia spelaea, and Naegleria pringsheimi, and optionally incorporating an internal ribosome entry site (IRES) for improved protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If mRNA is used for vaccines to enable temporary protein expression in cytoplasm, then ease of manufacture and safety are improved, but structural stability deteriorates
Solution Approach 1:
The patent modifies the chemical structure of mRNA by introducing a lariat-cap structure at the 5' end, which changes the structural parameters of the molecule. This modification enhances intracellular stability and half-life while maintaining the ease of manufacture advantage of mRNA technology
Solution Approach 2:
The patent creates a composite nucleic acid structure by combining the mRNA coding sequence with a lariat-cap forming sequence (such as GIR1 ribozyme). This composite structure integrates the functional advantages of both components: the protein-coding capability of mRNA and the stability-enhancing lariat-cap structure
2Productivity
If high dose of mRNA is administered to achieve sufficient protein expression due to short half-life, then productivity is improved, but harmful factors increase
Solution Approach 1:
The patent applies partial action by introducing a specific stabilizing element (lariat-cap structure) rather than using high doses of entire mRNA molecules. This partial modification at the 5' end provides sufficient stability enhancement to reduce the required dose, thereby reducing harmful factors while maintaining productivity
Solution Approach 2:
The lariat-cap structure acts as a protective element that is introduced beforehand to prevent rapid degradation of mRNA. This prior cushioning against enzymatic degradation extends half-life, allowing lower doses to achieve the same protein expression levels and reducing associated harmful effects
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The lariat-cap structure significantly increases mRNA stability within cells, allowing for reduced dosage and potentially safer, more effective mRNA vaccines and pharmaceutical compositions for disease prevention and treatment.
Implementation Method 1
The RNA sequence GIR1, which exists in the myxomycete Didymium iridis species, is known to perform the function of a ribozyme, and in particular, this RNA sequence induces a very unusual reaction that directly connects the first and third nucleotide sequences of RNA
Data Source
AI summary
Unlike DNA, mRNA has the advantage of enabling transient expression of a desired protein directly in the cytoplasm without having to enter the nucleus, and thus attempts to use mRNA vaccines are actively underway. However, mRNA has lower structural stability than DNA, and thus has limitations with respect to industrial application. Therefore, the present invention relates to a technology for remarkably improving intracellular stability and biogenesis of mRNA. An mRNA stabilization method and an mRNA stabilization composition, of the present invention, have the excellent effects of enhancing target nucleic acid stabilization and target protein expression in mRNA vaccines and the like, and thus are expected to be widely used in the health/medical field.