Artificial Nucleic Acid Molecules for Stable High-Expression RNA
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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 ubiquitous RNAses, which affect the efficacy of protein production and immune response induction.
Innovation Solution
Development of artificial nucleic acid molecules incorporating a 5′UTR element from the TOP gene, optionally with a histone stem-loop and 3′UTR, and a poly(A) sequence, designed to enhance stability and translational efficiency, thereby improving protein production and immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional nucleic acid molecules are used for gene therapy and genetic vaccination, then the methods can be applied to treat diseases and induce immune responses, but the RNA molecules are unstable and degraded by ubiquitous RNAses, limiting their efficacy
Solution Approach 1:
The patent extracts and incorporates specific stable structural elements from viral RNA genomes (such as the 5'UTR from HIV-1 or 5'UTR from hepatitis C virus) into the artificial nucleic acid molecules. These extracted elements serve as protective frameworks that resist degradation by RNAses, thereby improving the stability and reliability of the therapeutic RNA without compromising its functional capacity to produce proteins or induce immune responses.
2Productivity
If nucleic acid molecules are used to produce proteins, then protein expression can be achieved, but the expression levels are limited, reducing the efficacy of therapy or vaccination
Solution Approach 1:
The patent modifies key parameters of the nucleic acid molecule structure, including the 5'UTR sequence, coding region composition, and 3'UTR elements, to optimize translational efficiency. By changing these molecular parameters, the patent achieves enhanced protein production levels while maintaining the functional integrity of the encoded proteins for therapeutic or vaccinational purposes.
3Duration of action of stationary object
If genomic integration is used to ensure long-term expression, then protein production can be sustained, but the risk of harmful integration events increases
Solution Approach 1:
The patent replaces the mechanical process of genomic integration (where nucleic acids insert into host DNA) with an alternative mechanism based on non-integrating viral vectors or transient expression systems. This substitution maintains the ability to achieve sustained protein expression through controlled cellular processes while eliminating the harmful effects of random genomic integration, such as insertional mutagenesis.
Data Source
AI summary
The invention relates to an artificial nucleic acid molecule comprising at least one 5′UTR element which is derived from a TOP gene, at least one open reading frame, and preferably at least one histone stem-loop. Optionally the artificial nucleic acid molecule may further comprise, e.g. a poly(A)sequence, a poyladenylation signal, and/or a 3′UTR. The invention further relates to the use of such an artificial nucleic acid molecule in gene therapy and/or genetic vaccination.