Histone Stem-Loop and Poly(A) Sequence for mRNA Expression
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Solution Overview
Problem
Current gene therapy and genetic vaccination methods face challenges in achieving sufficient mRNA stability and translational efficiency, leading to suboptimal expression of encoded proteins, particularly in RNA-based applications compared to DNA vaccines and gene therapies.
Innovation Solution
A nucleic acid sequence comprising a coding region for a pathogenic antigen or protein, combined with a histone stem-loop and a poly(A) sequence or polyadenylation signal, enhances protein expression by synergistic action of these elements, regardless of their order or length.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If traditional DNA-based gene therapy approaches are used, then mRNA stability is improved, but translational efficiency and protein expression level are reduced
Solution Approach 1:
The patent merges the stable poly(A) tail structure with the highly translational histone stem-loop structure into a single nucleic acid molecule. This combination allows the mRNA to simultaneously achieve enhanced stability from the poly(A) tail and improved translational efficiency from the stem-loop, resolving the contradiction between stability and protein expression level.
Solution Approach 2:
The invention creates a composite mRNA structure that integrates multiple functional elements: the coding region, the stable poly(A) tail, and the translational stem-loop. This composite design combines the advantages of different structural elements to achieve both stability and high translational efficiency that neither element could provide alone.
2Productivity
If RNA-based gene therapy approaches are used, then translational efficiency is improved, but mRNA stability is reduced
Solution Approach 1:
The patent combines the translational stem-loop element with the stabilizing poly(A) tail in a single nucleic acid molecule. This merging allows the mRNA to benefit from both the high translational efficiency of stem-loop structures and the enhanced stability provided by poly(A) tails, thereby resolving the contradiction between translational efficiency and mRNA stability.
3Stability of the object's composition
If individual mRNA stabilization elements are used, then mRNA stability is improved, but translational efficiency remains suboptimal
Solution Approach 1:
The invention merges two distinct functional elements - the poly(A) tail for stability and the histone stem-loop for translational efficiency - into a single integrated nucleic acid structure. This combination allows both functions to work synergistically, achieving both high stability and high translational efficiency simultaneously, which neither element could achieve alone.
Data Source
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AI summary
The present invention relates to a nucleic acid sequence, comprising or coding for a coding region, encoding at least one peptide or protein comprising a pathogenic antigen or a fragment, variant or derivative thereof, at least one histone stem-loop and a poly(A) sequence or a polyadenylation signal. Furthermore the present invention provides the use of the nucleic acid for increasing the expression of said encoded peptide or protein. It also discloses its use for the preparation of a pharmaceutical composition, especially a vaccine, e.g. for use in the treatment of infectious diseases. The present invention further describes a method for increasing the expression of a peptide or protein comprising a pathogenic antigen or a fragment, variant or derivative thereof, using the nucleic acid comprising or coding for a histone stem-loop and a poly(A) sequence or a polyadenylation signal.