Splice Modulating Oligonucleotides for RAGE Isoform Regulation
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Solution Overview
Problem
Dysregulation of RAGE signaling is associated with various diseases due to excessive activation, leading to inflammatory responses and tissue damage, and existing therapies fail to effectively modulate RAGE expression or function to address these conditions.
Innovation Solution
The use of splice modulating oligonucleotides (SMOs) that specifically bind to RAGE pre-mRNA sequences to alter splicing patterns, increasing the production of soluble RAGE isoforms while decreasing membrane-bound RAGE isoforms, thereby reducing pathological signaling and ligand availability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing therapies are used to modulate RAGE expression or function, then treatment approaches are available, but they fail to effectively address RAGE dysregulation and its associated diseases
Solution Approach 1:
The invention changes the molecular parameter of RAGE isoform expression by using splice modulating oligonucleotides to shift the splicing equilibrium from membrane-bound to soluble isoforms, thereby altering the functional properties of the RAGE system without changing the overall RAGE gene expression level
Solution Approach 2:
The invention introduces splice modulating oligonucleotides as intermediary molecules that bind to RAGE pre-mRNA and redirect splicing, serving as a mediator between the RAGE gene and its protein products to achieve selective isoform modulation
2Reliability
If membrane-bound RAGE is overexpressed or over-activated, then RAGE signaling is enhanced, but this leads to inflammatory responses and tissue damage
Solution Approach 1:
The invention inverts the normal RAGE signaling paradigm by converting the harmful membrane-bound signaling form into the beneficial soluble decoy form through splice modulation, thereby reversing the pathological effects of RAGE over-activation
Solution Approach 2:
The invention converts the harmful over-activated membrane-bound RAGE signaling into beneficial soluble RAGE that acts as a decoy to sequester ligands and reduce inflammation, transforming a pathological state into a therapeutic one
3Object-generated harmful factors
If soluble RAGE is increased to act as a decoy, then ligand availability for membrane-bound RAGE is reduced, but this requires selective modulation of isoform production
Solution Approach 1:
The invention segments the RAGE gene expression pathway by targeting specific splicing events to produce distinct isoform populations, allowing independent control of soluble versus membrane-bound RAGE levels through separate molecular mechanisms
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
This approach effectively modulates RAGE splicing to decrease membrane-bound RAGE expression and increase soluble RAGE, acting as a decoy to reduce inflammatory signaling and ligand-induced damage, providing a therapeutic benefit for multiple diseases associated with RAGE dysregulation.
Implementation Method 1
The use of splice modulating oligonucleotides (SMOs) that specifically bind to RAGE pre-mRNA sequences to alter splicing patterns, increasing the production of soluble RAGE isoforms while decreasing membrane-bound RAGE isoforms
Data Source
AI summary
The invention provides splice modulating oligonucleotides (SMOs) designed to modulate the splicing of a RAGE pre-mRNA, compositions including the SMOs, and methods of treating and preventing diseases and conditions using the SMOs and compositions.