Antisense Oligonucleotide Gapmer Design for RPS25 Modulation
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Solution Overview
Problem
Current approaches to modulating RPS25 gene expression using antisense nucleic acids are limited in effectiveness, and there is a need for more potent RPS25 gene antisense oligonucleotides for pharmaceutical applications, particularly in reducing dipeptide repeat production associated with repeat diseases.
Innovation Solution
A single-stranded antisense oligonucleotide with a specific base sequence and modified nucleic acids, capable of binding to RPS25 mRNA, is developed. This oligonucleotide includes a gap region and wing regions with modified nucleic acids, forming a phosphorothioate bond, and is designed to hybridize under stringent conditions, facilitating RNase-driven degradation of the RPS25 gene.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense nucleic acids are used to modulate RPS25 gene expression, then gene expression modulation is achieved, but the effectiveness is limited and insufficient for pharmaceutical applications
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of the antisense oligonucleotide. Specifically, it introduces a gapmer structure with modified sugar moieties (2′-O-methyl and 2′-O-methoxyethyl) at the wing regions and phosphorothioate backbone modifications. These chemical parameter changes enhance the oligonucleotide's stability, binding affinity, and resistance to nucleases, thereby improving its effectiveness in modulating RPS25 gene expression and reducing dipeptide repeat production
Solution Approach 2:
The patent employs composite materials by creating a hybrid oligonucleotide structure that combines different nucleic acid components. The gapmer structure integrates a central gap region (DNA-like) with wing regions containing modified RNA-like sugars. This composite structure leverages the advantages of both DNA and RNA components, achieving enhanced stability, cellular uptake, and RNase H recruitment capability, which collectively improve the therapeutic effectiveness
2Object-generated harmful factors
If RPS25 gene expression is reduced to alleviate pathology, then dipeptide repeat production decreases, but the current antisense oligonucleotide approaches achieve only limited gene expression reduction
Solution Approach 1:
The patent implements feedback mechanisms through the design of the gapmer structure that recruits RNase H. The modified sugar moieties (2′-O-methyl and 2′-O-methoxyethyl) create a conformational structure that enhances RNase H binding and catalytic activity. This feedback loop ensures efficient cleavage of the target RPS25 mRNA, leading to substantial gene expression reduction and effective suppression of dipeptide repeat production
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 antisense oligonucleotide effectively modulates RPS25 gene expression, reducing dipeptide repeat production and offering a potential therapeutic benefit for repeat diseases such as C9orf72 ALS and Huntington's disease.
Implementation Method 1
a base sequence capable of hybridizing under stringent conditions with an oligonucleotide having the target region
Implementation Method 2
facilitating RNase-driven degradation of the RPS25 gene
Data Source
AI summary
A single-stranded antisense oligonucleotide, or a pharmaceutically acceptable salt thereof, capable of modulating expression and/or function of RPS25 gene, wherein nucleotides 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 optionally including a nucleic acid having a modified sugar moiety, each of the 3′ wing region and the 5′ wing region is a modified nucleotide, the single-stranded antisense oligonucleotide has a base length of 12- to 30-mer, and a base sequence of the 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 of the same base length as the antisense oligonucleotide present in the base sequence as set forth in SEQ ID NO: 1 or SEQ ID NO: 2; 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.