Oligonucleotide Sugar Modifications for ADAR-Mediated A-to-I Editing
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Solution Overview
Problem
Current oligonucleotide technologies for editing nucleic acids, particularly for adenosine modification, face challenges such as low efficiency, selectivity, stability, and immune stimulation, often requiring exogenous components and lacking optimal sugar and internucleotidic linkage modifications.
Innovation Solution
Design and composition of oligonucleotides with specific sugar modifications, internucleotidic linkages, and structural elements that utilize endogenous ADAR proteins for efficient and selective A-to-I editing, enhancing stability, selectivity, and cellular uptake, while minimizing immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If conventional oligonucleotide technologies are used for adenosine editing, then the basic editing function is achieved, but the efficiency is low
Solution Approach 1:
The patent applies parameter changes by systematically modifying sugar modifications (2'-F, 2'-OMe, 2'-MOE, LNA, cEt), internucleotidic linkages (phosphorothioate, phosphodithioate, morphotideoate), and their positional patterns to optimize ADAR protein binding and editing efficiency. These parameter variations resolve the contradiction by achieving high productivity through optimized chemical parameters while maintaining reliability through systematic evaluation of modification patterns.
Solution Approach 2:
The patent employs composite materials by combining multiple types of modifications (sugar modifications + internucleotidic linkage modifications + sequence design) within a single oligonucleotide molecule. This composite approach resolves the contradiction by integrating multiple functional elements that collectively enhance both editing efficiency and reliability, rather than relying on a single modification type.
2Stability of the object's composition
If oligonucleotides with high stability modifications are used, then stability is improved, but selectivity decreases
Solution Approach 1:
The patent applies local quality by placing specific modifications at particular positions within the oligonucleotide sequence rather than uniformly throughout. For example, certain sugar modifications are concentrated in specific regions to maintain stability while preserving selectivity at critical positions for ADAR recognition and editing. This positional differentiation resolves the contradiction between stability and selectivity.
Solution Approach 2:
The patent uses partial action by applying modifications selectively to only certain portions of the oligonucleotide rather than the entire sequence. This allows the modified regions to provide enhanced stability while unmodified or differently modified regions maintain the selectivity required for precise editing, thus resolving the contradiction between these two properties.
3Reliability
If exogenous components are used for editing, then editing activity can be achieved, but device complexity and toxicity increase
Solution Approach 1:
The patent applies self-service by designing oligonucleotides that recruit and utilize the cell's endogenous ADAR proteins to perform the editing function. Rather than delivering complex exogenous editing systems, the modified oligonucleotides themselves serve as the active component that harnesses existing cellular machinery, thereby achieving reliable editing activity while minimizing system complexity and potential toxicity.
Solution Approach 2:
The patent uses the endogenous ADAR protein as an intermediary between the oligonucleotide and the editing outcome. The modified oligonucleotide acts as a guide that mediates the interaction between the target RNA and the endogenous ADAR enzyme, enabling precise editing without requiring delivery of complex exogenous protein-nucleic acid complexes, thus reducing system complexity.
4Ease of operation
If natural RNA sugars are used for adenosine editing, then cellular uptake is good, but stability is low
Solution Approach 1:
The patent applies parameter changes by systematically varying sugar modification types (2'-F, 2'-OMe, 2'-MOE, LNA, cEt) and their positional patterns to optimize the balance between cellular uptake and stability. Certain sugar modifications at specific positions enhance cellular uptake while maintaining or improving stability, resolving the contradiction between these two properties through precise parameter optimization.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The described oligonucleotides demonstrate improved efficiency, selectivity, and stability in A-to-I editing, leveraging endogenous proteins to achieve high activity and reduced toxicity, with enhanced pharmacokinetic and pharmacodynamic properties.
Implementation Method 1
editing of target adenosine... conversion of A to I... modification of an A residue, e.g., converting an A to I
Data Source
AI summary
Among other things, the present disclosure provides oligonucleotides and compositions thereof. In some embodiments, provided oligonucleotides and compositions are useful for adenosine modification. In some embodiments, the present disclosure provides methods for treating various conditions, disorders or diseases that can benefit from adenosine modification.