Modified Oligonucleotide Compositions for Selective Adenosine Editing
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Solution Overview
Problem
Existing oligonucleotide technologies face challenges in efficiently editing nucleic acids, particularly in converting adenosine to inosine, with issues related to stability, selectivity, cellular uptake, immune stimulation, and toxicity, especially when relying on exogenous components.
Innovation Solution
Designing oligonucleotides with specific sugar modifications, nucleobase modifications, and internucleotidic linkages, such as 2′-F and 2′-OR modifications, along with chirally controlled internucleotidic linkages, to enhance editing efficiency and selectivity, stability, and reduce immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If exogenous components (proteins, nucleic acids, viruses) are used for nucleic acid editing, then editing activity can be achieved, but delivery complexity and immune stimulation increase
Solution Approach 1:
The patent utilizes endogenous ADAR proteins already present in cells to perform the editing function, eliminating the need to deliver exogenous editing proteins or nucleic acids. The oligonucleotide guide itself recruits the endogenous enzyme to the target site,实现ing self-service editing without complex delivery systems
Solution Approach 2:
The patent extracts only the essential guiding function into a simplified oligonucleotide molecule, separating the targeting function from the editing function. The oligonucleotide serves as a standalone guide that recruits endogenous enzymes, removing the complexity of delivering entire protein-nucleic acid complexes
2Reliability
If natural RNA sugars are used in oligonucleotides for adenosine editing, then editing activity is achieved, but stability is reduced
Solution Approach 1:
The patent applies sugar modifications selectively at specific positions within the oligonucleotide sequence, particularly at the 5' and 3' ends and at positions where stability is most needed. This local modification approach maintains editing activity while enhancing overall stability
Solution Approach 2:
The patent creates composite oligonucleotides combining modified sugars (such as 2'-F, 2'-OMe, 2'-MOE) with natural nucleobases and phosphate backbones. This composite structure provides both the stability of modified sugars and the biological functionality of natural components
3Productivity
If oligonucleotides are designed for high editing efficiency, then adenosine conversion is improved, but selectivity may be compromised
Solution Approach 1:
The patent optimizes multiple parameters including oligonucleotide length, sugar modification types and positions, base composition, and GC content to achieve the optimal balance between efficiency and selectivity. By carefully adjusting these parameters, the oligonucleotides achieve high editing efficiency while maintaining specificity for the target adenosine
Solution Approach 2:
The patent incorporates stability-enhancing modifications and selectivity-optimizing sequence designs during oligonucleotide synthesis, preparing the molecule in advance with optimal properties before cellular delivery. This preliminary optimization ensures both high efficiency and selectivity are built into the structure itself
4Duration of action of stationary object
If oligonucleotides with increased stability are designed, then half-life is improved, but cellular uptake may be reduced
Solution Approach 1:
The patent applies stability modifications primarily at the terminal regions and non-critical positions of the oligonucleotide, while keeping the central region with base modifications relatively unchanged. This localized approach to modification preserves cellular uptake efficiency while enhancing overall stability and half-life
Data Source
AI summary
The present disclosure features useful oligonucleotide compositions and methods related thereto. The present disclosure encompasses the recognition that structural elements of oligonucleotides, such as base sequence, chemical modifications (e.g. modifications of sugar, base and/or internucleotide linkages) or patterns thereof, can have a significant impact on oligonucleotide properties and activities. The present disclosure also provides methods to treat disorders for which deamination of an adenosine in an mRNA produces a therapeutic result, e.g., in a subject in need thereof.