Histone Stem-Loop and Poly(A) Sequence for mRNA Stability
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current gene therapy approaches face challenges in achieving sufficient mRNA stability and translational efficiency, leading to suboptimal expression of therapeutic proteins, particularly with RNA-based applications compared to DNA-based methods.
Innovation Solution
A nucleic acid sequence comprising a coding region for a therapeutic protein, a histone stem-loop, and a poly(A) sequence or polyadenylation signal is used to enhance protein expression, leveraging the synergistic effect of these elements to increase mRNA stability and translational efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional mRNA is used in gene therapy, then the mRNA can be introduced into cells to encode therapeutic proteins, but the mRNA stability is insufficient and translational efficiency is suboptimal
Solution Approach 1:
The patent combines a poly(A) sequence with a histone stem-loop structure to create a hybrid 3' UTR element. This merging of two distinct functional elements (poly(A) tail and stem-loop) results in synergistic effects that simultaneously enhance mRNA stability and translational efficiency, resolving the contradiction between reliability and productivity.
Solution Approach 2:
The invention uses a composite nucleic acid structure where the 3' UTR contains both poly(A) sequence and histone stem-loop motifs. This composite design integrates the stabilizing properties of poly(A) tails with the translational enhancement capabilities of stem-loop structures, achieving both improved stability and higher protein expression levels.
2Productivity
If RNA-based gene therapy approaches are used, then the therapeutic protein can be expressed in cells, but the expression level is lower compared to DNA-based methods
Solution Approach 1:
The patent modifies the 3' UTR parameters by incorporating specific sequences (poly(A) and histone stem-loop) that change the mRNA's structural and functional properties. These parameter changes in the nucleic acid sequence lead to enhanced stability and translational efficiency, enabling RNA-based approaches to achieve expression levels comparable to or exceeding DNA-based methods.
Data Source
AI summary
The present disclosure concerns a nucleic acid sequence, comprising or coding for a coding region, encoding at least one peptide or protein comprising a therapeutic protein or a fragment, variant or derivative thereof, at least one histone stem-loop and a poly(A) sequence or a polyadenylation signal. The present disclosure further concerns a method for increasing the expression of a peptide or protein comprising a therapeutic protein 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.