ADAR-Recruiting Oligonucleotide Chemistry for Selective RNA Editing
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Solution Overview
Problem
Existing synthetic single-stranded oligonucleotides lack the required selectivity and stability to effectively utilize ADAR proteins for therapeutically editing target RNAs.
Innovation Solution
Development of novel oligonucleotides with chemical modifications such as α-homo-DNA and 2′-O-methyl ribose, incorporating specific structural features to recruit ADAR proteins efficiently and deaminate adenosine in target RNAs, even with varying neighboring bases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If synthetic single-stranded oligonucleotides are used to utilize ADAR proteins for RNA editing, then the ability to edit target RNAs is achieved, but the selectivity and stability are insufficient for therapeutic use
Solution Approach 1:
The patent applies chemical modifications to change the physical and chemical parameters of the oligonucleotide. Specifically, it uses 2'-O-methyl ribose modifications at specific positions (including the editing site and neighboring positions) and phosphorothioate linkages to alter the oligonucleotide's stability, selectivity, and ability to recruit ADAR proteins, thereby resolving the contradiction between reliability and productivity
Solution Approach 2:
The patent implements local quality by applying different chemical modifications at specific locations within the oligonucleotide sequence. The editing site and its neighboring bases receive 2'-O-methyl ribose modifications, while other regions may have different modifications or be unmodified. This localized modification strategy optimizes ADAR recruitment and editing efficiency at the critical site while maintaining overall oligonucleotide stability
2Reliability
If chemical modifications such as α-homo-DNA and 2′-O-methyl ribose are incorporated into oligonucleotides, then the specificity and efficiency of ADAR protein recruitment is enhanced, but the structural complexity increases
Solution Approach 1:
The patent applies local quality by restricting chemical modifications to specific local regions (the editing site and neighboring positions) rather than modifying the entire oligonucleotide uniformly. This allows enhancement of ADAR recruitment specificity at the critical site while minimizing the overall structural complexity and synthesis difficulty
3Productivity
If the oligonucleotide sequence is designed with specific triplet structures to recruit ADAR, then the editing efficiency is improved, but the difficulty of detecting and measuring optimal sequences increases
Solution Approach 1:
The patent systematically varies key parameters of the triplet structure (the three nucleotides surrounding the editing site) to identify optimal sequences for ADAR recruitment. By modifying the identity and chemical structure of nucleotides at these critical positions, the patent achieves high editing efficiency while establishing design rules that simplify the detection and measurement process
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 novel oligonucleotides enhance the specificity and efficiency of ADAR proteins to selectively edit target RNAs, thereby addressing the technical problem of existing technologies, thereby enhancing the specificity and stability of ADAR proteins for therapeutically editing target RNAs.
Implementation Method 1
Adenosine deaminases acting on RNA (ADAR) are enzymes which bind to double-stranded RNA (dsRNA) and convert adenosine to inosine through deamination
Data Source
AI summary
The present disclosure features useful compositions and methods to treat disorders for which deamination of an adenosine in an mRNA produces a therapeutic result.