TNA Antisense Gapmers With PO Linkages for Stable Gene Silencing
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for stable, safe, and efficient antisense oligonucleotide-based therapeutic agents that can effectively modulate gene expression and resist nucleolytic degradation.
Innovation Solution
Introduce α-L-threofuranosyl (TNA) nucleosides into antisense oligonucleotides via phosphodiester (PO) internucleoside linkages, particularly in gapmer designs, to enhance stability and therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If phosphorothioate (PS) linkages are introduced into antisense oligonucleotides, then stability to nucleolytic degradation and protein binding are increased, but the oligonucleotides may exhibit off-target effects and toxicity
Solution Approach 1:
The patent changes the chemical parameter of the internucleoside linkage from phosphorothioate (PS) to phosphodiester (PO), and modifies the sugar component to TNA. This parameter change maintains nuclease resistance while reducing off-target effects and toxicity associated with PS linkages.
Solution Approach 2:
The patent creates a composite structure combining TNA nucleosides with phosphodiester linkages, forming a novel TNA-PO oligonucleotide that integrates the stability benefits of modified backbones with the safety profile of natural phosphodiester bonds.
2Stability of the object's composition
If TNA nucleosides are introduced via phosphorothioate (PS) linkages, then stability is improved, but the harmful side effects of PS linkages persist
Solution Approach 1:
The patent extracts the TNA nucleoside component from the PS-linked structure and re-introduces it via phosphodiester linkages, thereby separating the stability-enhancing TNA moiety from the toxicity-causing PS linkage.
Solution Approach 2:
The patent changes the linkage parameter from PS to PO while maintaining TNA nucleosides, thereby achieving stability without the harmful effects of sulfur substitution in the phosphate backbone.
3Object-affected harmful factors
If conventional phosphodiester linkages are used in antisense oligonucleotides, then safety is improved, but stability to nucleolytic degradation is insufficient
Solution Approach 1:
The patent creates a composite structure where TNA nucleosides are incorporated into a phosphodiester backbone, combining the safety of PO linkages with the enhanced stability provided by the TNA sugar modification.
Solution Approach 2:
The patent modifies the sugar parameter from conventional deoxyribose/ribose to TNA (threose nucleic acid), which enhances nuclease resistance while maintaining phosphodiester linkages for safety.
Data Source
AI summary
Described are antisense oligonucleotides comprising one or more α-L-threofuranosyl (TNA) nucleosides linked to an adjacent nucleoside via a phosphodiester (PO) internucleoside linkage, as well as methods to modulate the properties of antisense oligonucleotides by the introduction of such TNA nucleosides. These are particularly applicable to antisense gapmer oligonucleotides.