Oligonucleotide Seed Region Targeting for RNA Specificity
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Solution Overview
Problem
Current oligonucleotides used to regulate target RNAs, such as siRNAs and microRNAs, often result in off-target effects due to their promiscuity, leading to unintended effects on non-intended targets, and existing methods like antisense oligonucleotides and RNase H-mediated cleavage can cause unintended RNA cleavage.
Innovation Solution
Development of oligonucleotides that are complementary to specific sequences of target RNAs, capable of modulating RNAi activity, preventing microRNA regulation, or inducing RNase H cleavage to specifically target and regulate target RNAs, thereby reducing off-target effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If siRNAs are used to regulate target RNAs, then specificity can be controlled through complementarity, but off-target effects occur due to promiscuity
Solution Approach 1:
The patent applies local quality by designing oligonucleotides with specific structural features (such as modified sugar-phosphate backbones, locked nucleic acids, or peptide nucleic acids) at critical positions to enhance binding specificity to the seed region of microRNAs. This localized modification ensures that the oligonucleotide selectively binds to the intended target microRNA while avoiding off-target effects, thus resolving the contradiction between achieving high specificity and minimizing harmful off-target interactions.
2Adaptability or versatility
If microRNAs are used to regulate target RNAs, then gene regulation can be achieved, but promiscuity leads to regulation of multiple targets including non-intended ones
Solution Approach 1:
The patent extracts the problematic promiscuous binding capability of microRNAs by designing oligonucleotides that specifically target and neutralize the seed region of microRNAs. By removing or blocking this critical region, the oligonucleotide prevents the microRNA from binding to unintended targets while preserving the ability to regulate intended targets, thus resolving the contradiction between versatile gene regulation and avoiding unintended effects.
3Reliability
If antimirs are used to inhibit microRNA activity, then target RNA regulation can be achieved, but the promiscuous nature of microRNAs causes the antimir to affect multiple target RNAs
Solution Approach 1:
The patent applies segmentation by designing oligonucleotides that target specific segments (seed regions) of microRNAs rather than attempting to neutralize the entire microRNA molecule. This segmented approach allows for precise control over which microRNA is inhibited and which target RNAs are affected, thereby improving reliability of microRNA inhibition while minimizing the impact on non-intended targets through selective binding to specific structural regions.
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
These oligonucleotides effectively regulate target RNAs with reduced off-target effects, providing a more predictable and specific therapeutic approach by blocking microRNA binding sites or inducing targeted RNA degradation, enhancing therapeutic efficacy while minimizing unintended consequences.
Implementation Method 1
the oligonucleotides of the invention may affect the activity of target RNAs, in particular target mRNAs, by blocking microRNA binding sites or inducing targeted RNA degradation through complementary base pairing
Implementation Method 2
oligonucleotides that can activate RNase H cleavage of the target mRNA were developed
Data Source
AI summary
The present invention relates to oligonucleotides for modulation of target RNA activity. Thus, the invention provides oligonucleotides that bind to microRNA binding sites of target RNA. The oligonucleotides may activate RNase H or RNAi. In a preferred embodiment, the oligonucleotides prevents a micro RNA from binding to its binding site of the target RNA and thereby prevent the microRNA from regulating the target RNA. Such oligonucleotides have uses in research and development of new therapeutics.