mRNA Stabilization via Ribosomal Protein 3′-UTR Elements
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Solution Overview
Problem
Current gene therapy and genetic vaccination methods face challenges with the stability and translational efficiency of nucleic acid molecules, particularly RNA, due to degradation and limited expression levels, which affect the efficacy of disease treatment and prevention.
Innovation Solution
Incorporating a 3′-untranslated region (UTR) element derived from ribosomal protein genes into artificial nucleic acid molecules, such as mRNA, to enhance stability and translational efficiency, thereby improving protein expression and production.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If RNA is used for gene therapy and genetic vaccination, then high specificity and individual treatment options are achieved, but stability and translational efficiency are reduced due to degradation
Solution Approach 1:
The patent modifies the chemical structure of mRNA by incorporating modified nucleosides (such as pseudouridine, N1-methylpseudouridine, and 5-methylcytidine) to change the physical and chemical parameters of the molecule. These modifications reduce immunogenicity and increase stability against degradation by cellular nucleases, thereby resolving the contradiction between achieving treatment efficacy and maintaining molecular stability
Solution Approach 2:
The patent creates composite mRNA structures by combining modified nucleosides with specific sequence elements (such as 5′-UTR and 3′-UTR regions from viral genomes) and incorporating them into delivery systems like lipid nanoparticles. This composite approach enhances both stability and translational efficiency while maintaining the therapeutic function
2Productivity
If RNA is used for gene therapy, then high translational efficiency is achieved, but degradation occurs limiting expression duration
Solution Approach 1:
The patent employs modified nucleosides that alter the degradation kinetics of mRNA without significantly reducing translational efficiency. Modifications such as 2′-O-methyl and 2′-fluoro substitutions protect against exonuclease and endonuclease degradation, thereby extending the half-life and duration of protein expression while maintaining high productivity
Solution Approach 2:
The patent performs preliminary stabilization of mRNA through chemical modifications and structural optimizations before delivery to cells. By pre-protecting the mRNA from degradation mechanisms using modified nucleosides and optimized sequence elements, the patent ensures both sustained expression duration and maintained translational efficiency throughout the therapeutic window
Data Source
AI summary
The invention relates to an artificial nucleic acid molecule comprising at least one open reading frame and at least one 3′-untranslated region element (3′-UTR) element comprising a nucleic acid sequence which is derived from the 3′-UTR of a ribosomal protein gene. The invention further relates to the use of such an artificial nucleic acid molecule in gene therapy and/or genetic vaccination. Furthermore, the invention relates to the use of a 3′-UTR element comprising a nucleic acid sequence which is derived from the 3′-UTR of a ribosomal protein gene for enhancing, stabilizing and/or prolonging protein expression from a nucleic acid sequence comprising such 3′-UTR element.