Antisense Oligonucleotides Targeting Retained Introns
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Solution Overview
Problem
Current therapies for diseases related to insufficient gene expression do not effectively address the underlying issue of intron retention in transcripts, leading to reduced protein production.
Innovation Solution
The use of antisense oligonucleotides (ASOs) that target retained intron sequences in genes associated with disease, specifically designed to increase protein expression by modifying splicing and reducing the abundance of intron-retaining transcripts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If ASOs are used to down-regulate gene expression, then unwanted protein production is reduced, but the ability to treat diseases caused by insufficient protein expression is limited
Solution Approach 1:
The patent inverts the conventional function of ASOs from down-regulating gene expression to up-regulating it. By targeting retained introns that normally hinder proper splicing and protein production, the ASO converts a harmful element (retained intron) into a therapeutic target that, when suppressed, increases functional protein expression. This inversion enables treatment of diseases caused by insufficient protein expression while maintaining the ability to reduce unwanted protein production.
2Reliability
If ASOs target retained intron sequences to increase protein expression, then therapeutic effectiveness for insufficient protein expression diseases is improved, but the complexity of identifying suitable target genes increases
Solution Approach 1:
The patent employs a computational self-service approach where algorithms automatically analyze genome data to identify genes with retained introns suitable for ASO therapy. The system autonomously processes large datasets, applies filtering criteria (such as intron retention frequency thresholds), and generates candidate gene lists without requiring manual analysis. This automation reduces the complexity of target identification while maintaining high therapeutic effectiveness through rigorous data-driven selection.
3Productivity
If a substantial fraction of transcripts retain introns, then ASO therapy can significantly increase protein expression, but the specificity of ASO design becomes more challenging
Solution Approach 1:
The patent applies local quality by designing ASOs that target specific local regions within retained introns rather than the entire intron sequence. The computational system identifies optimal target sites within the intron that exhibit high retention frequency and are accessible to ASO binding. This localized targeting approach maintains high specificity for the intended gene while effectively increasing protein expression, as the ASO concentrates its effect on the most critical retention sites rather than attempting to control the entire intron.
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 significantly increases the expression of target proteins, thereby treating diseases associated with insufficient protein levels, as demonstrated by the identification of genes with a substantial fraction of transcripts retaining introns.
Implementation Method 1
introducing to the cell an oligonucleotide comprising an antisense sequence complementary to a retained intron of a transcript produced by the gene
Data Source
AI summary
The compositions and methods described herein are related to the identification of disease related genes, the expression of which involves a fraction of transcripts with a retained intron, comprising antisense oligonucleotides (ASO) compositions and methods that target genes which meet two criteria: the genes have a fraction of transcripts that retains an intron, and haploinsufficiency of the gene is associated with disease.