Oligonucleotide Sugar Modifications for ADAR-Mediated Editing
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Solution Overview
Problem
Current oligonucleotide technologies for editing nucleic acids, particularly for modifying adenosine to inosine, face challenges in efficiency, selectivity, stability, and cellular uptake, often requiring exogenous components and resulting in immune stimulation and toxicity.
Innovation Solution
Design of oligonucleotides with specific sugar modifications, nucleobase modifications, and internucleotidic linkage configurations that utilize endogenous ADAR proteins for site-directed editing, enhancing efficiency, selectivity, and stability while minimizing immune response and toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotides with natural RNA sugars are used for adenosine editing, then high editing activity is achieved, but stability is poor
Solution Approach 1:
The patent applies local quality by introducing sugar modifications (2'-F, 2'-OMe, 2'-MOE) at specific positions within the oligonucleotide sequence rather than uniformly modifying all positions. This allows the oligonucleotide to maintain regions of natural structure for ADAR protein recognition and binding while incorporating modified sugars in strategic locations to enhance stability and resist nucleases, thereby resolving the contradiction between editing activity and stability.
Solution Approach 2:
The patent employs composite materials by combining multiple types of sugar modifications (2'-fluoro, 2'-O-methyl, 2'-O-methoxyethyl) within a single oligonucleotide molecule. This composite approach creates a hybrid structure that integrates the stability benefits of different modified sugars while maintaining the functional capacity for adenosine editing, thus achieving both high stability and retained editing activity.
2Stability of the object's composition
If oligonucleotides are modified to improve stability, then stability increases, but editing efficiency decreases
Solution Approach 1:
The patent applies local quality by introducing sugar modifications (2'-F, 2'-OMe, 2'-MOE) at specific positions within the oligonucleotide sequence rather than uniformly modifying all positions. This allows the oligonucleotide to maintain regions of natural structure for ADAR protein recognition and binding while incorporating modified sugars in strategic locations to enhance stability and resist nucleases, thereby resolving the contradiction between editing activity and stability.
Solution Approach 2:
The patent employs parameter changes by systematically varying the type, position, and extent of sugar modifications to optimize the balance between stability and editing efficiency. By adjusting these parameters—such as using 2'-F modifications at terminal positions for stability while keeping central regions less modified for protein interaction—the patent achieves enhanced stability without significant loss of editing efficiency.
3Reliability
If exogenous components are used for nucleic acid editing, then editing capability is achieved, but immune stimulation and toxicity increase
Solution Approach 1:
The patent applies self-service by designing oligonucleotides that harness the cell's own endogenous ADAR proteins to perform the editing function. Instead of delivering complex exogenous editing machinery that triggers immune responses, the modified oligonucleotides simply need to bind to the target RNA and recruit naturally occurring ADAR enzymes, thereby achieving editing capability while minimizing immune stimulation and toxicity.
Solution Approach 2:
The patent employs an intermediary approach by using modified oligonucleotides as mediators that bridge the gap between the target RNA and endogenous ADAR proteins. These oligonucleotides with specific sugar modifications serve as intermediaries that facilitate the interaction between the editing machinery and target sequence without requiring direct delivery of exogenous proteins or complex systems, thus reducing immunogenicity while maintaining editing capability.
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 designed oligonucleotides demonstrate improved editing efficiency, selectivity, and stability, achieving high adenosine modification activity with reduced immune stimulation and toxicity, and improved pharmacokinetic and pharmacodynamic properties.
Implementation Method 1
utilization of endogenous proteins such as ADAR (Adenosine Deaminases Acting on RNA) proteins (e.g., ADAR1 and/or ADAR2), for editing nucleic acids, e.g., for modifying an A (e.g., as a result of G to A mutation)
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.