Antisense Oligomers for SCN1A Splicing and NMD Exon Skipping
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Solution Overview
Problem
Nervous system disorders associated with channelopathies, such as Dravet Syndrome, are caused by mutations in the SCN1A gene leading to aberrant splicing and nonsense-mediated RNA decay, resulting in reduced expression of functional SCN1A protein.
Innovation Solution
The use of antisense oligomers (ASOs) that target specific regions of the NMD exon mRNA encoding SCN1A protein to modulate splicing, preventing the inclusion of nonsense-mediated RNA decay-inducing exons and increasing the level of processed mRNA and protein expression.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If mutations occur in the SCN1A gene, then channelopathy develops leading to nervous system disorders, but aberrant splicing and nonsense-mediated RNA decay reduce SCN1A protein expression
Solution Approach 1:
The patent extracts and removes the harmful NMD-inducing exon from the pre-mRNA transcript through targeted splicing modulation. The antisense oligomer specifically binds to sequences flanking the NMD-inducing exon to promote its exclusion from the mature mRNA, thereby extracting the harmful element that causes nonsense-mediated RNA decay and restoring functional SCN1A protein expression
Solution Approach 2:
The patent introduces an antisense oligomer as an intermediary molecule that mediates between the pre-mRNA and the splicing machinery. This oligomer contains sequences complementary to regions flanking the NMD-inducing exon and acts as a mediator to redirect splicing factors, promoting exon skipping and preventing the formation of harmful truncated transcripts
2Reliability
If antisense oligomers target specific regions of NMD exon mRNA to modulate splicing, then functional SCN1A protein expression increases, but the complexity of therapeutic agent design and delivery increases
Solution Approach 1:
The patent segments the therapeutic approach into distinct functional components: the antisense oligomer is divided into specific sequence regions that target flanking areas of the NMD-inducing exon rather than the exon itself. This segmentation allows for optimized binding affinity and splicing modulation while reducing off-target effects and simplifying the overall therapeutic design
Solution Approach 2:
The patent utilizes parameter changes in the antisense oligomer design, specifically optimizing the sequence composition, length, and target region parameters to maximize splicing modulation efficiency. By changing these parameters to target regions upstream and downstream of the NMD-inducing exon rather than the exon itself, the therapy achieves enhanced protein expression with reduced complexity in delivery requirements
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
Enhances the expression of functional SCN1A protein by up to 10-fold, potentially alleviating symptoms of conditions like Dravet Syndrome and other SCN1A-related disorders.
Implementation Method 1
the therapeutic agent binds to a targeted portion of the NMD exon mRNA encoding SCN1A
Data Source
AI summary
Alternative splicing events in SCN1A gene can lead to non-productive mRNA transcripts which in turn can lead to aberrant protein expression, and therapeutic agents which can target the alternative splicing events in SCN1A gene can modulate the expression level of functional proteins in Dravet Syndrome patients and/or inhibit aberrant protein expression. Such therapeutic agents can be used to treat a condition caused by SCN1A, SCN8A or SCN5A protein deficiency.