RPS25 Gapmer Antisense Oligonucleotide for Lower Central Toxicity
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Solution Overview
Problem
Existing antisense oligonucleotides used to modulate RPS25 gene expression suffer from delayed central toxicity, and there is a need for a solution that effectively reduces this toxicity while maintaining efficacy.
Innovation Solution
A single-stranded antisense oligonucleotide with a modified nucleic acid having a cyclopropane ring at the 5' position of the sugar moiety in the gap region, combined with modified nucleic acids in the wing regions, is designed to bind specifically to RPS25 gene, reducing delayed central toxicity and enhancing binding affinity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense oligonucleotides are used to modulate RPS25 gene expression, then gene modulation efficacy is achieved, but delayed central toxicity occurs
Solution Approach 1:
The patent applies local quality by modifying specific regions of the antisense oligonucleotide differently: the gap region contains deoxyribose-based nucleic acids for RNase H recruitment, while the wing regions contain modified nucleic acids with enhanced nuclease resistance. This regional differentiation optimizes both efficacy and safety profile by localizing specific functions to specific structural elements.
Solution Approach 2:
The patent employs composite materials by combining different types of nucleic acid modifications within a single oligonucleotide molecule. The structure integrates deoxyribose-based nucleic acids in the gap region with modified nucleic acids (having substituents at 2' position) in the wing regions, creating a composite structure that achieves both high gene modulation efficacy and reduced delayed central toxicity.
2Strength
If gapmer antisense oligonucleotides with phosphorothioate bonds are used, then binding affinity and nuclease resistance are improved, but hepatotoxicity and off-target toxicity increase
Solution Approach 1:
The patent reduces hepatotoxicity by localizing phosphorothioate bonds primarily in the gap region rather than distributing them throughout the entire oligonucleotide. The wing regions use modified nucleic acids with different chemical properties, creating a gradient of chemical reactivity that maintains binding affinity while reducing off-target interactions in the liver.
Solution Approach 2:
The patent changes chemical parameters by replacing phosphorothioate bonds with phosphodiester bonds in the wing regions, and by using modified nucleic acids with substituents at the 2' position. These parameter changes reduce the chemical reactivity that causes hepatotoxicity while maintaining sufficient binding affinity through the concentrated phosphorothioate bonds in the gap region.
3Stability of the object's composition
If modified nucleic acids with 2' position substituents are used in wing regions, then nuclease resistance is enhanced, but molecular flexibility is reduced
Solution Approach 1:
The patent applies local quality by concentrating modified nucleic acids with 2' position substituents in the wing regions where nuclease resistance is most needed, while keeping the gap region with deoxyribose-based nucleic acids more flexible. This spatial differentiation allows the molecule to maintain both high stability in the wing regions and sufficient flexibility in the gap region for proper target binding.
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 antisense oligonucleotide effectively modulates RPS25 gene expression with reduced delayed central toxicity, functioning as a catalyst for RNase-driven degradation and providing sustained effects with minimal dosage.
Implementation Method 1
a gapmer exhibits its effect by hybridizing with a target RNA sequence and inhibiting the gene expression
Implementation Method 2
functioning as a catalyst for RNase-driven degradation
Data Source
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AI summary
A single-stranded antisense oligonucleotide, or a pharmaceutically acceptable salt thereof, capable of modulating expression and/or function of RPS25 gene, wherein nucleosides of the single-stranded antisense oligonucleotide are bonded to each other via a phosphate group and/or a modified phosphate group, the single-stranded antisense oligonucleotide includes a gap region, a 3' wing region bonded to a 3' end of the gap region, and a 5' wing region bonded to a 5' end of the gap region, the gap region is a deoxyribose-based nucleic acid , which may contain a nucleic acid having a modified sugar moiety, the gap region includes at least one 5'-CP nucleic acid, each of the 3' wing region and the 5' wing region is a modified nucleic acid having a substituent at 2' position, the single-stranded antisense oligonucleotide is composed of 12 to 30 bases, and a base sequence of the single-stranded antisense oligonucleotide is: a base sequence with a sequence identity of 90% to 100% to a base sequence complementary to at least one target region having the same base length as the single-stranded antisense oligonucleotide present in a base sequence as set forth in SEQ ID NO: 1; a base sequence complementary to a base sequence of the target region with deletion, substitution, insertion, or addition of one or several bases; or a base sequence capable of hybridizing under stringent conditions with an oligonucleotide having the target region.