Antisense Oligonucleotide With BNA Wings for Chondroitin Sulfate Inhibition
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Solution Overview
Problem
Current treatments for spinal cord injuries are ineffective in inhibiting the production of chondroitin sulfate, which acts as a strong inhibitor of axon regeneration, hindering recovery.
Innovation Solution
Development of a highly functional antisense oligonucleotide that targets and suppresses the expression of the chondroitin sulfate N-acetylgalactosaminyl-transferase-1 (CSGalNAcT1) gene, specifically designed with a gap region and wing regions containing bridged nucleic acids, to inhibit chondroitin sulfate biosynthesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antisense oligonucleotides are used to inhibit chondroitin sulfate biosynthesis, then some inhibition effect is achieved, but the functionality and efficacy are insufficient
Solution Approach 1:
The antisense oligonucleotide is divided into three functional segments: a gap region (7-17 nucleotides) capable of binding to target mRNA, and 5′-wing and 3′-wing regions (2-6 nucleotides each) containing bridged nucleic acids. This segmentation allows each region to perform specialized functions, with the gap region providing target recognition and the wing regions providing structural stability and nuclease resistance, thereby achieving high inhibition efficacy without excessive overall complexity
Solution Approach 2:
The oligonucleotide employs a composite structure combining different nucleic acid types: natural nucleotides in the gap region and bridged nucleic acids (scpBNA or AmNA) in the wing regions. This composite approach integrates the advantages of each component - natural nucleotides for target complementarity and bridged nucleic acids for enhanced stability - resulting in superior functional performance
2Ease of manufacture
If the oligonucleotide structure is simplified for ease of manufacture, then manufacturing becomes easier, but the functional efficacy is reduced
Solution Approach 1:
The oligonucleotide applies local quality by concentrating the complex bridged nucleic acid modifications specifically in the 5′- and 3′-wing regions while keeping the central gap region as natural nucleotides. This localized complexity ensures that the critical target-binding region remains simple and manufacturable, while the modified wing regions provide the necessary stability and functionality, achieving a balance between ease of manufacture and gene suppression efficacy
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 reduces chondroitin sulfate levels, promoting axon regeneration and improving motor function recovery in spinal cord injury models, without affecting heparan sulfate levels.
Implementation Method 1
an antisense oligonucleotide that suppresses expression of the chondroitin sulfate N-acetylgalactosaminyl-transferase-1 (CSGalNAcT1) gene
Data Source
AI summary
This invention provides a highly functional antisense oligonucleotide that inhibits biosynthesis of chondroitin sulfate. The invention also provides an antisense oligonucleotide that suppresses expression of the chondroitin sulfate N-acetylgalactosaminyl-transferase-1 (CSGalNAc-T1) gene and has the properties (i) to (iv): (i) an antisense oligonucleotide is 13- to 25-mer in length; (ii) an antisense oligonucleotide comprises a gap region, a 3′-wing region bound to the 3′ end of the gap region, and a 5′-wing region bound to the 5′ end of the gap region; (iii) nucleotides in the 3′-wing region and in the 5′-wing region include at least one bridged nucleic acid and the bridged nucleic acid is scpBNA or AmNA; and (iv) an antisense oligonucleotide comprises a nucleotide sequence selected from the group consisting of SEQ ID NOs: 2 to 31 or a sequence derived therefrom by substitution, deletion, or insertion of 1 or 2 nucleic acid bases.