Chemically Modified ASOs for Stable, Specific Adenosine Editing
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Solution Overview
Problem
Existing antisense oligonucleotides (ASOs) face challenges in stability, cellular delivery and uptake, clinical efficacy, and off-target effects, limiting their widespread clinical success in treating genetic disorders.
Innovation Solution
Development of chemically modified ASOs with specific nucleoside and linkage modifications, including 2′-position sugar modifications and backbone linkages, to enhance stability and specificity, reducing off-target edits.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chemically modified ASOs with specific nucleoside and linkage modifications are developed, then stability and specificity are enhanced, but device complexity increases
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical parameters of the ASO molecule, including 2′-position sugar modifications (2′-O-methyl, 2′-fluoro), backbone linkage modifications (phosphorothioate, phosphorodiamidate), and base modifications. These parameter changes enhance stability against nucleases and improve binding specificity to target RNA, directly resolving the contradiction between reliability and complexity by optimizing chemical parameters.
Solution Approach 2:
The patent employs composite materials by combining multiple chemical modifications within a single ASO molecule. The oligonucleotide comprises a hybrid structure integrating modified sugars, modified phosphodiester linkages, and modified bases, creating a composite material that achieves enhanced stability and specificity while managing the inherent complexity through systematic integration.
2Stability of the object's composition
If chemically modified ASOs are developed to improve stability, then manufacturing complexity increases
Solution Approach 1:
The patent uses parameter changes to optimize manufacturing by standardizing the chemical modification patterns. The specific 2′-O-methyl and 2′-fluoro modifications at defined positions, combined with phosphorothioate linkages at specific regions, create a reproducible manufacturing protocol that balances stability enhancement with production feasibility.
Solution Approach 2:
The patent applies segmentation by dividing the ASO molecule into regions with different modification patterns: a 5′ region with specific modifications, a central region containing the target-binding sequence, and a 3′ region with tailored modifications. This segmentation allows modular synthesis and assembly, reducing manufacturing complexity while maintaining overall stability.
3Productivity
If ASOs are designed for high editing efficacy, then off-target effects may increase
Solution Approach 1:
The patent applies local quality by implementing different modification patterns at different positions within the ASO sequence. The 2′-O-methyl modifications are placed at specific positions to enhance binding affinity and reduce off-target effects, while 2′-fluoro modifications are positioned to maximize editing efficacy at the target site. This localized optimization of quality parameters resolves the contradiction between productivity and harmful effects.
Solution Approach 2:
The patent uses parameter changes to fine-tune the balance between editing efficacy and off-target effects by adjusting the degree of chemical modification at specific positions. The phosphorothioate linkage density and 2′-modification patterns are optimized to enhance target binding while minimizing non-specific interactions, directly addressing the contradiction between high productivity and reduced harmful factors.
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 modified ASOs demonstrate improved editing efficacy, increased lysosomal stability, and ease of production, while minimizing off-target effects.
Implementation Method 1
capable of binding to a target sequence in a target RNA
Implementation Method 2
allowing a mammalian ADAR enzyme to deaminate a target adenosine present in a target RNA sequence to an inosine
Data Source
AI summary
The invention relates to chemically modified oligonucleotides comprising a sequence with a length of 23 to 80 nucleotides, capable of binding to a target sequence in a target RNA, comprising a central base triplet (CBT) of 3 nucleotides (5′—N−1eN0fN+1g-3′) with the central nucleotide (N0) directly opposite to the target adenosine in the target RNA, wherein the core oligonucleotide comprises the following sequence: 5′—N−5aN−4b N−3cN−2dN−1eN0fN+1gN+2h N+3 iN+4j-3′ comprising different 2′ sugar and linkage modifications. The present disclosure also provides oligonucleotides and compositions thereof for use in use in the treatment or prevention of a genetic disorder, condition, or disease. Also provided are methods for editing a target adenosine or deaminating at least one specific adenosine in a target nucleic acid.