Modified Poly(A) Structure for Stable mRNA Translation
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Solution Overview
Problem
Natural poly(A) sequences in mRNA exhibit instability and variability, leading to inconsistent translation efficiency and stability, which complicates mRNA drug development and quality control.
Innovation Solution
A modified poly(A) polynucleotide with specific nucleotide configurations, including at least two R elements of A nucleotides and one or more S elements, is introduced to stabilize mRNA and enhance translation efficiency.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural poly(A) is used in mRNA, then the mRNA can be synthesized and translated, but the poly(A) length varies randomly causing instability and inconsistent translation efficiency
Solution Approach 1:
The poly(A) sequence is divided into multiple A blocks separated by non-A nucleotides (S elements). Each A block contains a specific number of A nucleotides (e.g., 6-12 A's), and they are separated by S elements consisting of 1-4 non-A nucleotides. This segmentation prevents random length variation while maintaining the functional properties of poly(A) for mRNA stability and translation efficiency.
Solution Approach 2:
The invention changes the parameters of poly(A) by introducing a defined structure with specific numbers of A nucleotides in each block (6-12), specific lengths of S elements (1-4 non-A nucleotides), and a total poly(A) length of 30-150 nucleotides. This parameter control ensures consistent poly(A) length across different mRNA molecules, resolving the randomness issue of natural poly(A).
2Reliability
If modified poly(A) with specific structure is introduced, then mRNA stability and translation efficiency are improved, but the poly(A) structure becomes more complex
Solution Approach 1:
The poly(A) sequence is divided into multiple A blocks separated by non-A nucleotides (S elements). Each A block contains a specific number of A nucleotides (e.g., 6-12 A's), and they are separated by S elements consisting of 1-4 non-A nucleotides. This segmentation prevents random length variation while maintaining the functional properties of poly(A) for mRNA stability and translation efficiency.
Solution Approach 2:
The invention changes the parameters of poly(A) by introducing a defined structure with specific numbers of A nucleotides in each block (6-12), specific lengths of S elements (1-4 non-A nucleotides), and a total poly(A) length of 30-150 nucleotides. This parameter control ensures consistent poly(A) length across different mRNA molecules, resolving the randomness issue of natural poly(A).
Data Source
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AI summary
A polynucleotide, the polynucleotide comprising a modified poly(A) having at least 30 nucleotides. The modified poly(A) comprises: i) at least two R elements, the R elements being defined as polynucleotide composed of A nucleotide; and ii) at least one S element. The S element: a) is a nucleotide that is not an A nucleotide, or b) is composed of at least two nucleotides, and the nucleotides at both ends are not A nucleotide. The total number of S elements is one less than the total number of R elements, the S elements are connected to the R elements, and each S element is flanked by the R elements. The present invention also relates to a vector and a host cell comprising the polynucleotide, a method for using the polynucleotide to prepare RNA and the RNA prepared therefrom, a pharmaceutical composition or LNP comprising the polynucleotide, the RNA, the vector, and/or the host cell, and a use thereof.