SCN1A Antisense Compounds for NaV1.1 Splicing in Dravet Syndrome
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Solution Overview
Problem
Mutations in the SCN1A gene lead to reduced expression or function of NaV1.1 protein, contributing to conditions like Dravet Syndrome, for which there is a need for compounds that can modulate alternative splicing events to increase functional protein expression.
Innovation Solution
Development of compounds, such as antisense oligomers (ASOs), that target nonsense-mediated mRNA decay-inducing exons in the SCN1A gene to promote the exclusion of these exons from pre-mRNA, thereby increasing the expression of functional NaV1.1 protein.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for Dravet Syndrome, then seizure management is attempted, but NaV1.1 protein expression remains reduced and disease progression continues
Solution Approach 1:
The patent employs antisense oligomers as intermediary molecules that bind to specific exon sequences in the SCN1A pre-mRNA, directing the splicing machinery to exclude harmful exons (exons 13, 14, or 20) from the mature mRNA. This intermediary approach allows precise manipulation of splicing outcomes to restore functional NaV1.1 protein expression without directly modifying the gene sequence or using complex gene therapy vectors.
Solution Approach 2:
The invention changes the splicing parameters by introducing antisense oligomers that alter the thermodynamic and kinetic parameters of RNA-protein interactions during splicing. By modifying the binding affinity and specificity of splicing factors through antisense oligomer design, the patent achieves shifted splicing equilibria that favor inclusion of productive exons and exclusion of harmful exons, thereby changing the output parameter of functional protein expression.
2Adaptability or versatility
If nonsense-mediated decay-inducing exons are included in SCN1A pre-mRNA, then alternative splicing occurs, but functional NaV1.1 protein expression is reduced
Solution Approach 1:
Antisense oligomers serve as intermediaries that selectively bind to nonsense-mediated decay-inducing exons, preventing their inclusion in mature mRNA. These oligomers mediate the interaction between the splicing machinery and specific exon sequences, directing the exclusion of harmful exons while preserving alternative splicing adaptability for other exons that may have physiological roles.
Solution Approach 2:
Instead of attempting to force inclusion of harmful exons or using complex methods to restore gene function, the invention inverts the approach by targeting and excluding the specific harmful exons through antisense oligomers. This inversion strategy simplifies the problem from trying to achieve productive splicing of all exons to selectively removing the problematic ones, thereby restoring functional protein expression.
3Reliability
If gene therapy approaches are used to increase NaV1.1 expression, then protein levels may be improved, but treatment complexity and potential side effects increase
Solution Approach 1:
The patent uses antisense oligomers as simpler intermediary molecules compared to complex gene therapy vectors. These oligomers can be administered systemically and act through well-understood splicing modulation mechanisms, avoiding the need for viral vectors, transgenic animals, or complex genomic integration procedures. This intermediary approach maintains therapeutic effectiveness while significantly reducing treatment complexity and associated risks.
Data Source
AI summary
Compounds are provided herein that can promote expression of a specific gene, SCN1A. In some aspects, provided herein are compositions, methods, and kits relating to the compounds disclosed herein. In some aspects, compounds provided herein can target the alternative splicing events in SCN1A gene and can modulate the expression level of functional proteins in Dravet Syndrome patients and/or inhibit aberrant protein expression. Such compounds can be used to treat a condition caused by SCN1A, SCN8A or SCN5A protein deficiency.