Cyclic Antisense Oligonucleotide Structure for PRR Evasion
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Solution Overview
Problem
Existing antisense oligonucleotides face challenges with nuclease stability and inflammatory responses, limiting their therapeutic index and efficacy due to interactions with Pattern Recognition Receptors (PRRs), despite advancements in modifications like phosphorothioate and hairpin loops.
Innovation Solution
Development of cyclic structured oligonucleotides (CSOs) where two oligonucleotides are linked, forming an intramolecular cyclic structure that masks the 5′-end, reducing interaction with PRRs and enhancing nuclease stability, allowing for improved specificity and reduced inflammatory responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If phosphorothioate modifications are introduced to improve nuclease stability, then stability is improved, but inflammatory responses increase due to PRR interactions
Solution Approach 1:
The patent extracts the harmful 5'-end from the oligonucleotide structure by creating a cyclic backbone where the 5'-end is covalently linked to the 3'-end, eliminating the free 5'-end that interacts with PRRs while retaining the therapeutic antisense function
Solution Approach 2:
The patent creates a composite cyclic oligonucleotide structure combining phosphorothioate modifications for stability with a cyclic topology that prevents PRR recognition, achieving both nuclease stability and reduced immunogenicity
2Stability of the object's composition
If 3'-end modifications are introduced to improve nuclease stability, then stability is improved, but therapeutic potency is not improved and inflammatory responses increase
Solution Approach 1:
Instead of modifying the 3'-end as conventionally done, the patent inverts the approach by creating a cyclic structure where the linkage is between 5'-end and 3'-end, fundamentally changing the molecular architecture to achieve both stability and potency
3Stability of the object's composition
If hairpin loop structures are introduced to improve nuclease stability, then stability is improved, but inflammatory responses increase thereby limiting therapeutic index
Solution Approach 1:
The patent segments the linear oligonucleotide into a cyclic structure with distinct functional domains (antisense domain, cyclizing domain) connected by a backbone, where the cyclic architecture provides stability without the inflammatory side effects of hairpin loops
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
CSOs exhibit enhanced nuclease stability and reduced immune activation, maintaining therapeutic potency by forming a cyclic structure that unfolds to target RNA, thereby minimizing off-target effects and improving therapeutic index.
Implementation Method 1
antisense hybridization and affinity influence selectivity for the targeted RNA
Implementation Method 2
the cyclizing domain comprises a nucleotide sequence that is complementary to a portion of the functional domain
Implementation Method 3
nuclease stability is important which has been provided by the modification of internucleotide linkages, for example, phosphorothioate
Implementation Method 4
The cyclic structure masks the 5′-end, reducing interaction with PRRs
Implementation Method 5
DNA phosphorothioate antisense, when hybridized to RNA, activates RNase H
Data Source
AI summary
The present invention provides oligonucleotides referred to as cyclic structured oligonucleotides (“CSOs”) comprising a functional domain, a cyclizing domain, and a linker segment as described herein, compositions comprising same, and methods of using same. This design of cyclic oligonucleotides maintains a cyclic form until it is in the presence of and hybridizes with a targeted RNA.