Oligonucleotide Ethylene Glycol Modification for Stability and Silencing Control
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Solution Overview
Problem
Existing chemical modifications on oligonucleotides, such as siRNA, often lead to non-silencing or excessive silencing of target mRNA, resulting in unwanted side effects or lack of therapeutic benefit, and also hinder long-term in vivo silencing.
Innovation Solution
The use of ethylene glycol chemical modifications on modified oligonucleotides to modulate silencing activity, allowing for robust or modest silencing over varying time periods, and to improve the stability of these oligonucleotides.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If existing chemical modifications are used on oligonucleotides, then stability is improved, but silencing activity becomes uncontrolled (non-silencing or excessive silencing)
Solution Approach 1:
The patent applies parameter changes by systematically varying the type, position, and number of ethylene glycol modifications on the oligonucleotide to optimize both stability and silencing activity. Different modification patterns (e.g., 2′-O-ethylene glycol, backbone ethylene glycol) are tested to find the optimal balance between these two parameters.
Solution Approach 2:
The patent uses composite materials by combining multiple chemical modifications on the oligonucleotide, including ethylene glycol modifications alongside other stabilizing modifications like 2′-fluoro, 2′-O-methyl, and phosphorothioate modifications, to achieve both enhanced stability and controlled silencing activity.
2Duration of action of moving object
If existing chemical modifications are used on oligonucleotides, then therapeutic duration is extended, but silencing precision deteriorates (leading to unwanted side effects or lack of therapeutic benefit)
Solution Approach 1:
The patent applies local quality by placing ethylene glycol modifications at specific positions within the oligonucleotide sequence rather than uniformly throughout. This localized modification strategy allows different regions of the oligonucleotide to have different properties, maintaining silencing precision in critical regions while enhancing stability and duration in other regions.
Solution Approach 2:
The patent systematically changes parameters including the position, number, and type of ethylene glycol modifications to optimize the balance between therapeutic duration and silencing precision, achieving robust silencing (75% or greater) or modest silencing (25% to 50%) as needed.
3Stability of the object's composition
If ethylene glycol modifications are increased to improve stability, then oligonucleotide stability increases, but silencing activity may be reduced
Solution Approach 1:
The patent applies partial action by using moderate numbers of ethylene glycol modifications (e.g., 1-5 modifications per oligonucleotide) rather than excessive modification, which would overly stabilize the molecule and prevent it from performing its silencing function. This partial modification approach achieves the right balance.
Solution Approach 2:
The patent changes parameters by varying the number of ethylene glycol modifications to find the optimal point where stability is sufficiently improved without compromising silencing activity, achieving both robust and modest silencing effects as needed.
Data Source
AI summary
The disclosure relates to compositions, systems, and methods comprising ethylene glycol chemical modifications on oligonucleotides to modulate silencing activity and improve stability.