tRNA Fragments Modulate TLR7 Signaling
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Solution Overview
Problem
Current methods for boosting immunity, particularly through TLR7 modulation, face challenges due to toxicity issues with synthetic compounds, and there is a need for natural ligands that can effectively activate toll-like receptors with lower cellular toxicity.
Innovation Solution
Administering nucleic acid molecules comprising fragments or variants of tRNA molecules, specifically designed to activate TLR7 or TLR8, which are derived from natural tRNA halves, to enhance immune responses and treat diseases such as cancer and infectious conditions.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If synthetic compounds are used to modulate TLR7 for boosting immunity, then immune response enhancement is achieved, but cellular toxicity increases
Solution Approach 1:
The patent uses endosomal TLR7 and TLR8 as intermediary receptors to naturally recognize and respond to viral ssRNA ligands, mediating immune activation without requiring synthetic compounds. This natural recognition system eliminates the toxicity associated with synthetic TLR7 modulators while maintaining effective immune response enhancement through endogenous signaling pathways
Solution Approach 2:
The invention employs short-lived, naturally occurring viral ssRNA ligands that are processed and degraded within the endosomal compartment after activating TLR7/8. These transient RNA molecules provide acute immune stimulation without persistent toxicity, allowing the system to reset and avoid cumulative cellular damage associated with longer-lasting synthetic compounds
2Object-affected harmful factors
If natural ligands are used to activate TLR7, then cellular toxicity is reduced, but the availability and characterization of effective ligands remain limited
Solution Approach 1:
The patent identifies that multiple different viral ssRNA ligands from various pathogens (flaviviruses, alphaviruses, coronaviruses, etc.) can all activate the same endosomal TLR7 and TLR8 receptors. This universality means a single receptor system can respond to diverse viral threats, and by extension, synthetic or engineered ligands can be designed to target this conserved pathway, expanding ligand availability while maintaining low toxicity
Solution Approach 2:
The invention explores how variations in ssRNA parameters (sequence composition, length, secondary structure, modifications) affect TLR7/8 activation efficiency. By systematically changing these parameters in natural viral RNAs or designing synthetic analogs, researchers can optimize ligand properties to enhance activation while maintaining the low toxicity profile of natural ligands, thus expanding the available toolset
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 use of tRNA-derived nucleic acid molecules effectively activates toll-like receptors, enhancing immune responses with potentially lower toxicity, providing a promising approach for immunotherapy and disease treatment.
Implementation Method 1
endosomal TLR7 and -8 recognize single-stranded RNAs (ssRNAs)... TLR7 and -8 are primarily expressed in immune cells such as monocytes/macrophages, dendritic cells, neutrophils, and B cells, and their recognition of pathogen-derived ssRNAs (e.g., viral and bacterial ssRNAs) recruits MyD88, activates NF-κB-mediated transcription, and induces the production of interferons and cytokines
Data Source
AI summary
The present invention provides fragments of tRNA molecules and methods of use thereof to modulate toll like receptor (TLR) signaling, for immunotherapy and for other therapeutic applications.