3′-End Oligonucleotide Stabilization for In Vivo mRNA Persistence
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Solution Overview
Problem
Nucleic acids such as mRNA have low stability in vivo due to degradation by nucleases, leading to a rapid decrease in concentration and reduced medical efficacy.
Innovation Solution
Introducing an oligonucleotide or its derivative with a specific structure to the 3′-end of the polynucleotide, such as mRNA, to enhance stability, using a polynucleotide represented by specific formulas with a 5′-cap structure and a phosphodiester bond at the 3′-end.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mRNA is administered to subjects, then medical efficacy is achieved through protein biosynthesis, but stability in vivo is low due to nuclease degradation
Solution Approach 1:
The patent introduces a stabilizing sequence as an intermediary element that mediates between the mRNA and nucleases. This specific nucleotide sequence acts as a protective intermediary that reduces nuclease accessibility and degradation, thereby improving in vivo stability while preserving the mRNA's ability to function
Solution Approach 2:
The patent modifies the nucleotide sequence parameters by introducing specific stabilizing sequences with particular compositional characteristics (such as GC content, secondary structure formation, and specific motif sequences). These parameter changes in the sequence composition enhance resistance to degradation without compromising the coding function
2Duration of action of moving object
If mRNA concentration is maintained in vivo, then medical efficacy is sustained, but concentration rapidly decreases due to degradation
Solution Approach 1:
The stabilizing sequence is incorporated into the mRNA structure in advance (preliminarily) before administration. This preliminary structural modification prepares the mRNA for extended survival in vivo by pre-establishing protective features that prevent rapid degradation, thereby sustaining concentration over time
Solution Approach 2:
The stabilizing sequence enables continuous maintenance of functional mRNA concentration in vivo. By preventing degradation, the sequence ensures that the mRNA continues to perform its protein-synthesis function over an extended period, maintaining continuous useful action rather than rapid decay
Data Source
AI summary
Disclosed are a polynucleotide with improved stability in vivo, a producing method thereof, and a method of improving the stability of polynucleotide in vivo.