Oligonucleotide Tertiary Structure Immune Modulation
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Solution Overview
Problem
Current treatments with cytokines and oligonucleotides for inflammatory and autoimmune diseases often face challenges such as significant side effects and immunogenicity, with a need for more effective methods to induce specific cytokine expression without unwanted activities.
Innovation Solution
Development of oligonucleotides that modulate the immune system by adopting specific tertiary structures, such as telomeric G-quadruplex tetramer or non-G-quadruplex dimer structures, to induce specific cytokine profiles like IFN-α, IFN-β, IFN-γ, IL-6, and IL-10, independent of their primary sequence, allowing for targeted immune modulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cytokine treatments are used to treat inflammatory and autoimmune diseases, then therapeutic effect is achieved, but significant side effects and immunogenicity occur
Solution Approach 1:
The invention changes the fundamental parameter of treatment from protein-based cytokines to nucleic acid-based oligonucleotides with specific tertiary structures. This parameter change allows induction of endogenous cytokine production rather than direct administration of cytokines, thereby achieving therapeutic effects while avoiding the immunogenicity and side effects associated with exogenous cytokine treatments
Solution Approach 2:
The oligonucleotides act as intermediaries that induce the host's own cells to produce cytokines endogenously. Instead of directly administering cytokines that cause immunogenicity, the oligonucleotides serve as mediators that trigger the body's natural cytokine production mechanisms, thereby achieving the desired immune modulation without the harmful effects of exogenous cytokine administration
2Adaptability or versatility
If oligonucleotides are designed to induce specific cytokine expression, then targeted immune modulation is achieved, but complexity in identifying effective sequences increases
Solution Approach 1:
The invention shifts the focus from primary sequence design to tertiary structure design. Instead of searching through vast sequence spaces to find effective oligonucleotides, the approach is to design oligonucleotides that fold into specific tertiary structures (G-quadruplexes, triple helices, etc.). This parameter change from sequence-centric to structure-centric design dramatically reduces the complexity of identifying effective oligonucleotides while maintaining targeted immune modulation capability
Solution Approach 2:
The invention establishes that multiple different primary sequences can fold into the same functional tertiary structure and produce the same immunomodulatory effect. This universality means that once a functional tertiary structure is identified, many different sequence variants can be used, reducing the complexity of sequence identification while maintaining versatility in targeted immune modulation
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 stimulate cytokine production, offering a more targeted and potentially less toxic approach to treating inflammatory and autoimmune diseases by inducing specific cytokine profiles, thereby improving treatment efficacy while minimizing side effects.
Implementation Method 1
G-quartets arise from the association of four adjacent G-bases assembled into a cyclic conformation. These structures are stabilized by von Hoogsteen hydrogen bonding and by base stacking interactions
Implementation Method 2
G-quartets arise from the association of four adjacent G-bases assembled into a cyclic conformation. These structures are stabilized by von Hoogsteen hydrogen bonding and by base stacking interactions
Implementation Method 3
These oligonucleotides effectively stimulate cytokine production, offering a more targeted and potentially less toxic approach to treating inflammatory and autoimmune diseases by inducing specific cytokine profiles
Data Source
Figure 1A~1C
Figure 1D~1F
Figure 1G~1H
AI summary
The present invention relates to methods of identifying oligonucleotides capable of modulating the immune system in a mammalian subject, comprising analysis of which tertiary structural type said oligonucleotide adopts, in phosphate-buffered saline solution. Further, the invention provides oligonucleotides identifiable by the methods of the invention and to their use in methods of treating diseases, such as inflammatory diseases, autoimmune diseases, infectious diseases, neurodegenerative diseases and cancer.