RAGE Pre-mRNA Splicing Modulation With Antisense Oligonucleotides
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Solution Overview
Problem
Current methods lack the ability to specifically target and modulate the alternative splicing of RAGE, which is implicated in various diseases, leading to aberrant RAGE signaling and dysfunction.
Innovation Solution
The use of splice-switching antisense oligonucleotides (AONs) that are complementary to specific regions of the RAGE pre-mRNA, including introns and splice sites, to induce exon skipping or intron retention, thereby modulating the expression of functional or decoy RAGE isoforms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If splice-switching antisense oligonucleotides are used to modulate RAGE splicing, then specific RAGE isoforms can be generated to antagonize ligand-dependent and ligand-independent activation, but the complexity of the molecular biology techniques and the precision required for designing effective AONs increase
Solution Approach 1:
The patent uses antisense oligonucleotides as intermediary molecules that bind to specific regions of RAGE pre-mRNA to modulate splicing. These AONs act as mediators between the researcher's intent and the desired splicing outcome, enabling precise control over RAGE isoform generation without requiring direct manipulation of the splicing machinery itself.
Solution Approach 2:
The patent employs parameter changes in the design of antisense oligonucleotides, including variations in sequence composition, length, and chemical modifications. By optimizing these parameters, the patent achieves effective splicing modulation while managing the complexity of AON design and delivery.
2Adaptability or versatility
If AONs target introns and splice sites to induce exon skipping or intron retention, then functional or decoy RAGE isoforms can be generated, but the precision required for AON design and the difficulty of detecting and measuring splicing effects increase
Solution Approach 1:
The patent applies local quality by designing AONs with specific sequences that target particular intronic regions or splice sites. Each AON is customized to bind to a specific location in the RAGE pre-mRNA, enabling selective modulation of particular splicing events while leaving other regions unaffected. This localized approach allows versatile isoform generation with manageable design complexity.
3Strength
If RAGE expression is upregulated in response to injury, stress, hypoxia or inflammation, then pro-inflammatory and pro-proliferative signaling is enhanced, but this contributes to the development and progression of inflammatory and metabolic disorders
Solution Approach 1:
The patent employs inversion by generating decoy RAGE isoforms that lack the ability to activate pro-inflammatory signaling pathways. These inverted or reversed functional forms of RAGE act as dominant-negative molecules that can bind ligands but cannot propagate harmful signals, thereby inverting the normal pro-inflammatory function into a protective or neutral function.
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 regulates RAGE splicing, generating cyto-protective isoforms that can antagonize ligand-dependent and ligand-independent activation, providing therapeutic benefits for diseases associated with RAGE, such as neurodegenerative diseases, cancer, and inflammatory disorders.
Implementation Method 1
The use of splice-switching antisense oligonucleotides (AONs) that are complementary to specific regions of the RAGE pre-mRNA
Data Source
AI summary
An isolated or purified AON for modifying pre-mRNA splicing in the Receptor for Advanced Glycation End-products (RAGE) to modulate splicing of the RAGE gene transcript or part thereof is provided.