AECM-Modified Oligonucleotides Enhance Cellular Uptake and Stability
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Solution Overview
Problem
Current oligonucleotide therapies face limitations due to the lability of oligonucleotides in biological fluids and poor delivery to the site of action, which affects their efficiency in regulating gene expression, particularly for diseases caused by mis-spliced RNA, as they often require recognition by cellular degrading enzymes.
Innovation Solution
Development of modified oligonucleotides with a substantial degree of 2′-O—(N-(aminoethyl)carbamoyl)methyl (AECM) modification, which enhances cellular uptake and stability, allowing for tighter binding to target RNA without recognition by nucleases, thereby improving drug delivery and therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotides are modified to increase stability and binding affinity, then therapeutic efficacy is improved, but cellular uptake is reduced
Solution Approach 1:
The patent applies parameter changes by systematically modifying the oligonucleotide structure through 2'-O-alkyl modifications (methyl, ethyl, isopropyl groups) and phosphorothioate backbone modifications. These chemical parameter changes optimize the balance between stability and cellular uptake, where the 2'-O-methyl modification specifically enhances stability while the phosphorothioate modifications improve cellular penetration, resolving the contradiction between stability and uptake efficiency
Solution Approach 2:
The patent creates composite oligonucleotide structures by combining multiple modification types: 2'-O-alkyl modifications on the ribose moiety, phosphorothioate modifications on the phosphate backbone, and mixed DNA/RNA sequences. This composite approach allows different parts of the oligonucleotide to contribute different properties - the 2'-O-alkyl groups provide stability and binding affinity, while the phosphorothioate modifications enhance cellular uptake, thereby resolving the technical contradiction
2Productivity
If oligonucleotides are designed for recognition by cellular degrading enzymes, then gene expression regulation is improved, but delivery to site of action is poor
Solution Approach 1:
The patent uses parameter changes by introducing phosphorothioate modifications where non-bridging oxygen atoms are replaced with sulfur atoms. This chemical parameter change protects the oligonucleotide from degradation by cellular nucleases while maintaining the ability to regulate gene expression through RNA interference or antisense mechanisms, thereby improving both delivery stability and regulatory efficiency
Solution Approach 2:
The patent applies segmentation by creating mixed oligonucleotide sequences containing both DNA and RNA segments, with specific regions modified for stability and other regions designed for enzyme recognition. The 2'-O-alkyl modifications are applied selectively to certain nucleotides while leaving other regions unmodified or differently modified, allowing different segments to fulfill different functions - some segments protect from degradation while others enable gene regulation, resolving the contradiction between delivery and productivity
3Stability of the object's composition
If 2'-O-alkyl modifications are introduced to increase duplex stability, then binding affinity to target RNA is improved, but nuclease resistance is reduced
Solution Approach 1:
The patent merges two different modification strategies: 2'-O-alkyl modifications (which enhance duplex stability) and phosphorothioate modifications (which provide nuclease resistance). By combining these modifications in the same oligonucleotide molecule, the patent achieves both high binding affinity to target RNA and strong resistance to nuclease degradation, resolving the contradiction between duplex stability and nuclease resistance
Solution Approach 2:
The patent creates a composite modified oligonucleotide where 2'-O-alkyl groups are incorporated into the ribose moiety to enhance duplex stability and binding affinity, while phosphorothioate modifications are introduced into the phosphate backbone to provide nuclease resistance. This composite structure allows the oligonucleotide to simultaneously achieve high duplex stability and strong nuclease resistance, resolving the technical contradiction
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 AECM modification increases the melting point of oligonucleotide duplexes and enhances cellular uptake, leading to improved stability and delivery of oligonucleotides, making them suitable for oligonucleotide-based therapies and potentially as vectors for other drugs.
Implementation Method 1
The AECM modification increases the melting point of oligonucleotide duplexes
Implementation Method 2
allowing for tighter binding to target RNA
Implementation Method 3
without recognition by nucleases
Data Source
AI summary
The present invention relates to modified oligonucleotides of 5-50 nucleotide residues, wherein at least 25% of the nucleotides are independently modified at the 2′ position to comprise the structure of formula (I), wherein base is a purine or pyrimidine moiety; and R1, R2, R3, R4, p and q are as defined in the description. The modified oligonucleotides comprising said structures are useful as medicaments for enhancement of drug uptake in oligonucleotide based therapy in humans and animals.