Antisense Oligonucleotide Terminal Modification Reduces Hepatotoxicity
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Solution Overview
Problem
Antisense oligonucleic acids exhibit severe hepatotoxicity due to delivery to the liver, making it challenging to design sequences that are both effective and safe for therapeutic use, as existing methods struggle to balance binding affinity and specificity with nuclease resistance and reduced toxicity.
Innovation Solution
The development of antisense oligonucleotides with specific modifications, such as 2′,4′-bridged nucleic acids and modified bases like 5-hydroxycytosine, which reduce hepatotoxicity while maintaining high binding affinity and stability, by incorporating these modifications into specific regions of the oligonucleotide sequence.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If antisense oligonucleic acid is administered intravenously to treat disease, then it can suppress expression of target genes, but it causes severe hepatotoxicity due to delivery to the liver
Solution Approach 1:
The patent applies local quality by modifying only specific bases at terminal positions (positions 1-3 and 19-21) rather than the entire oligonucleic acid sequence. This localized modification approach reduces hepatotoxicity while preserving the binding affinity and therapeutic efficacy of the central unmodified region that hybridizes to target mRNA.
Solution Approach 2:
The patent changes chemical parameters by introducing modified bases (such as 5-methylcytosine, 5-hydroxymethylcytosine, 6-methylpurines) at terminal positions. These parameter changes alter the molecular properties of the oligonucleic acid to reduce recognition by hepatic nucleases and decrease hepatotoxicity while maintaining overall structure and function.
2Reliability
If antisense oligonucleic acid is designed with high binding affinity to target mRNA, then it can effectively suppress gene expression, but it becomes more susceptible to nuclease degradation in vivo
Solution Approach 1:
The patent applies local quality by concentrating stability-enhancing modifications at terminal positions while keeping the central binding region unmodified. This allows the oligonucleic acid to maintain high binding affinity to target mRNA through the unmodified central region while gaining nuclease resistance from the modified terminal regions that are less critical for hybridization.
Solution Approach 2:
The patent creates a composite structure combining modified and unmodified nucleic acid regions. The modified terminal regions provide nuclease resistance while the unmodified central regions maintain optimal binding affinity, creating a composite molecule that achieves both stability and efficacy.
3Object-affected harmful factors
If the oligonucleic acid sequence is modified to reduce hepatotoxicity, then safety is improved, but binding affinity and specificity may be compromised
Solution Approach 1:
The patent applies local quality by restricting modifications to terminal positions (1-3 and 19-21) that are less critical for target mRNA hybridization. This allows the central region (positions 4-18) to maintain high binding affinity and specificity through unmodified bases, while terminal modifications reduce hepatotoxicity.
Solution Approach 2:
The patent segments the oligonucleic acid into functional regions: modified terminal regions for safety and protection, and unmodified central regions for binding. This segmentation allows independent optimization of each region's properties without compromising the other.
Data Source
AI summary
The present invention aims to provide an antisense oligonucleic acid with reduced hepatotoxicity. The antisense oligonucleic acid according to the present invention is characterized in that it has a base length of not less than 7 nt and not more than 30 nt, wherein nucleic acid residues of not less than 1 nt and not more than 5 nt respectively from the both terminals are 2′,4′-bridged nucleic acids, 2′,4′-non-bridged nucleic acid residue(s) is(are) present between the above-mentioned both terminals, and one or more bases in the nucleic acid residue(s) of the above-mentioned 2′,4′-non-bridged nucleic acid residue(s) is/are modified.