Artificial Nucleic Acid Molecules With Dual Poly(A) Tails for Expression
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Solution Overview
Problem
Current gene therapy and genetic vaccination methods using nucleic acid molecules face challenges such as genomic integration risks, limited expression levels, and instability of RNA, particularly due to degradation by RNases, which affect the efficacy of protein production and immune response.
Innovation Solution
Development of artificial nucleic acid molecules, specifically mRNA species, incorporating a 3′-UTR with a poly(A) sequence or polyadenylation signal, to enhance stability and translation efficiency, thereby improving protein production and immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If RNA is used for gene therapy and genetic vaccination, then the risk of genomic integration is reduced, but the stability of the nucleic acid molecule deteriorates due to degradation by RNases
Solution Approach 1:
The patent introduces an artificial nucleic acid molecule as an intermediary between DNA and natural RNA. This molecule uses DNA as the backbone (avoiding RNase degradation) while incorporating a poly(A) sequence at the 3'-end (mimicking eukaryotic mRNA features). The poly(A) sequence acts as a mediator that enables proper translation and stability without requiring the molecule to be actual RNA, thus resolving the contradiction between avoiding genomic integration and maintaining stability.
Solution Approach 2:
The patent changes the chemical parameter of the nucleic acid backbone from ribose (RNA) to deoxyribose (DNA), fundamentally altering the stability profile. This parameter change makes the molecule resistant to RNase degradation while maintaining the ability to be translated into protein through the inclusion of a poly(A) sequence that facilitates proper translation initiation and stability.
2Reliability
If traditional nucleic acid molecules are used, then the risk of genomic integration occurs with DNA, but the expression levels remain limited
Solution Approach 1:
The patent modifies the 3'-end structure parameter of the nucleic acid molecule by adding a poly(A) sequence. This structural parameter change enhances translation efficiency and protein expression levels while maintaining the DNA backbone that prevents genomic integration. The poly(A) sequence mimics eukaryotic mRNA features, enabling better recognition by the translation machinery without altering the fundamental safety profile of using DNA rather than RNA.
3Productivity
If RNA is used to achieve high translation efficiency, then the protein production increases, but the loss of substance increases due to rapid degradation
Solution Approach 1:
The patent uses an artificial nucleic acid molecule as an intermediary that combines the stability of DNA with the translational efficiency features of RNA. By using a DNA backbone with a poly(A) sequence, the molecule avoids RNase degradation entirely while still enabling high protein production through proper translation initiation and elongation mechanisms that recognize the poly(A) structure.
Solution Approach 2:
The patent effectively creates a stable, long-lasting nucleic acid molecule that does not require continuous replenishment. By eliminating the rapid degradation pathway present in RNA, the artificial nucleic acid molecule persists longer in the system, continuously driving protein production without being rapidly consumed and degraded by RNases.
Data Source
AI summary
The invention relates to a method for stimulating an immune response by intramuscular injection of an artificial nucleic acid molecule comprising an open reading frame encoding an antigen and a 3′-UTR comprising at least two poly(A) sequences. The method may yield an increased immune response to the antigen or an increased neutralizing antibody response to the antigen.