Artificial Nucleic Acid Molecules Using Ribosomal 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 instability and limited expression levels, which can lead to premature degradation and reduced immune response.
Innovation Solution
Incorporating a 3'-untranslated region (3'-UTR) element derived from ribosomal protein genes into artificial nucleic acid molecules, such as mRNA, to enhance stability and translational efficiency, while maintaining or improving protein production levels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If RNA is used for gene therapy or genetic vaccination, then the risk of undesired genomic integration and generation of anti-DNA antibodies is minimized or avoided, but RNA is considered to be a rather unstable molecular species which may readily be degraded by ubiquitous RNAses
Solution Approach 1:
The patent introduces 3'-UTR elements derived from stable endogenous mRNAs as intermediary components that mediate between the unstable exogenous RNA and the cellular environment. These 3'-UTR elements act as protective adapters that recruit cellular stabilizing factors and protect the RNA from degradation, thereby resolving the contradiction between safety and stability.
Solution Approach 2:
The patent changes the stability parameter of RNA by incorporating specific 3'-UTR sequences from endogenous mRNAs with known stability characteristics. This parameter change transforms the inherently unstable RNA into a stable molecular species suitable for therapeutic applications, while maintaining the safety advantages of RNA-based approaches.
2Duration of action of stationary object
If the half-life of mRNA is extended by stabilizing the 3'-end, then protein production is prolonged, but it may have an attenuating effect on translation
Solution Approach 1:
The patent applies local quality by selecting 3'-UTR elements with specific characteristics that provide stability without translation attenuation. Different 3'-UTR elements are evaluated and selected based on their local properties - some provide stability while others maintain high translation efficiency, allowing optimization for specific applications.
Solution Approach 2:
The patent systematically varies the 3'-UTR sequence parameter to achieve optimal balance between half-life extension and translation efficiency. By testing multiple 3'-UTR variants, the patent identifies sequences that extend mRNA half-life while maintaining or enhancing translation, thereby resolving the contradiction between duration and productivity.
3Productivity
If 3'-UTR elements from ribosomal protein genes are used to stabilize mRNA, then protein production is enhanced, but the complexity of nucleic acid molecule design increases
Solution Approach 1:
The patent establishes universality by identifying 3'-UTR elements from ribosomal protein genes that can be universally applied to stabilize various mRNA molecules regardless of their coding sequences. These universal 3'-UTR elements can be combined with different open reading frames to create stable therapeutic mRNAs, simplifying the overall design process despite the initial complexity.
Data Source
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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.