RNA-editing oligonucleotides and uses thereof
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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 relevant RNA editing.
Innovation Solution
Development of oligonucleotides with specific structural features, including 2′-O-methyl modifications and phosphorothioate/phosphoramidate linkages, to enhance ADAR recruitment and editing efficiency, particularly targeting adenosine residues in RNA.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional synthetic single-stranded oligonucleotides are used to target adenosine in RNA, then the basic RNA editing function is achieved, but the selectivity and stability are insufficient for therapeutic applications
Solution Approach 1:
The patent applies local quality by introducing specific chemical modifications at particular positions within the oligonucleotide sequence. The 2′-O-methyl modifications are placed at specific positions (e.g., positions 2-8 and 18-24) rather than uniformly throughout, and phosphorothioate linkages are introduced at specific locations (e.g., positions 1-5 and 26-30). This localized modification strategy enhances selectivity and stability at critical regions while minimizing overall structural complexity and maintaining compatibility with ADAR protein binding.
Solution Approach 2:
The patent employs composite materials by combining multiple chemical modification types within a single oligonucleotide structure. The oligonucleotide comprises a hybrid backbone with both phosphodiester and phosphorothioate linkages, along with 2′-O-methyl modified nucleosides at specific positions. This composite structure integrates the stability benefits of phosphorothioate linkages with the enhanced RNA binding affinity of 2′-O-methyl modifications, creating an optimized therapeutic agent that overcomes the limitations of conventional unmodified oligonucleotides.
2Productivity
If oligonucleotides are designed to recruit ADAR proteins for RNA editing, then the editing efficiency is improved, but the structural complexity of the oligonucleotide increases
Solution Approach 1:
The patent applies parameter changes by systematically varying chemical modification parameters to optimize ADAR recruitment and editing efficiency. Specifically, the patent tests different patterns of 2′-O-methyl modifications (positions 2-8 vs. positions 18-24), different ratios of phosphorothioate to phosphodiester linkages (30-70%), and different sequence contexts surrounding the target adenosine. These parameter optimizations enhance editing efficiency while controlling structural complexity through rational design rather than exhaustive modification.
Solution Approach 2:
The patent uses the chemically modified oligonucleotide structure as an intermediary that facilitates the interaction between the guide sequence and the ADAR protein. The 2′-O-methyl modifications and phosphorothioate linkages act as mediators that enhance the stability of the RNA:oligonucleotide duplex and improve recruitment of ADAR proteins to the target site, thereby increasing editing efficiency without requiring complex multi-component systems.
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 demonstrate enhanced recruitment of ADAR proteins, leading to efficient and selective deamination of adenosine in target RNAs, potentially offering therapeutic benefits.
Implementation Method 1
ADARs are editing enzymes that recognize certain structural motifs of double-stranded RNA (dsRNA) and edit adenosine to inosine, resulting in recoding of amino acid codons
Data Source
AI summary
The present disclosure features useful compositions and methods to treat disorders for which deamination of an adenosine in an RNA produces a therapeutic result in a subject in need thereof.