Antisense Oligomer Modulation of Poison Exons in Monogenic Disorders
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Solution Overview
Problem
Current treatments for monogenic disorders such as KBG syndrome and Sotos syndrome are limited, and existing methods struggle to efficiently modulate alternative splicing to restore functional mRNA and protein production, particularly due to the challenge of identifying and targeting relatively abundant 'poison exons' that contribute to unproductive transcripts.
Innovation Solution
The use of antisense oligomers (ASOs) that bind to specific regions of precursor mRNA to modulate the splicing of poison exons, thereby increasing or decreasing the production of functional mRNA and protein, targeting identified abundant poison exons in genes like ANKRD11 and NSD1 to treat conditions like KBG syndrome, Sotos syndrome, and other diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatment methods are used for monogenic disorders, then current symptom management is provided, but effective treatment options are limited and functional protein production cannot be restored
Solution Approach 1:
The patent changes the molecular parameter of splicing fidelity by introducing ASOs that selectively bind to poison exons, altering the splicing outcome from inclusion to exclusion. This parameter change enables restoration of functional protein production in monogenic disorders where conventional treatments cannot modify the underlying molecular defect.
Solution Approach 2:
The patent extracts and removes the harmful element (poison exon) from the mRNA transcript through ASO-mediated exon skipping. By selectively eliminating the poison exon that causes unproductive transcripts, the method restores functional protein production, addressing the limitation of conventional symptom management approaches.
2Productivity
If alternative splicing modulation is attempted to restore functional protein, then protein production can be increased, but identification and targeting of relatively abundant poison exons remains challenging
Solution Approach 1:
The patent performs preliminary identification and characterization of poison exons with abundant expression before designing ASO therapies. By pre-characterizing which poison exons are sufficiently abundant to be therapeutic targets, the method streamlines the subsequent targeting process and improves the efficiency of restoring functional protein production.
Solution Approach 2:
The patent replaces complex genomic analysis methods with a more direct ASO-based approach that targets and modulates splicing of identified poison exons. This substitution simplifies the overall process of restoring functional protein by directly addressing the splicing defect rather than relying on complex genetic modification approaches.
3Quantity of substance
If poison exons are targeted to suppress unproductive transcripts, then functional mRNA and protein levels increase, but the complexity of designing and implementing the modulation strategy increases
Solution Approach 1:
The patent segments the complex task of monogenic disorder treatment into discrete steps: (1) identification of poison exons, (2) design of ASOs targeting specific poison exons, (3) administration of ASOs, and (4) measurement of functional protein restoration. This segmentation simplifies the overall strategy by breaking down the complex modulation process into manageable, sequential steps.
Solution Approach 2:
The patent introduces ASOs as intermediary molecules that mediate between the goal of restoring functional protein and the challenge of targeting poison exons. The ASOs serve as deliverable therapeutic agents that can be administered to patients, simplifying the implementation complexity compared to direct genetic modification approaches.
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 upregulates or downregulates protein expression, as demonstrated by significant increases in mRNA and protein levels in both in vitro and in vivo models, providing a promising therapeutic strategy for these disorders.
Implementation Method 1
contacting the cells with an antisense oligomer (ASO) complementary to a targeted portion of the precursor mRNA
Data Source
AI summary
A method of increasing or decreasing expression of a target mRNA and protein for treatment of certain disease conditions by cells having a pre-mRNA that comprises a poison exon and encodes the target protein, and can include contacting the cells with an antisense oligomer (ASO) complementary to a targeted portion of the pre-mRNA.