SCN8A Splice Modulating Oligonucleotides for Dravet Disorder
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Solution Overview
Problem
Current treatments for Dravet Spectrum disorders, caused by SCN1A mutations, are inadequate due to non-specific effects on sodium channel function, necessitating a precise modulation of SCN8A subunit contributions to sodium channel function.
Innovation Solution
Development of splice modulating oligonucleotides (SMOs) that specifically target SCN8A pre-mRNA to modulate splicing, reducing SCN8A function and rebalancing excitatory/inhibitory imbalances in the brain by altering the expression of SCN8A isoforms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If general sodium channel blockers are used to treat Dravet Spectrum disorders, then seizure activity is reduced, but non-specific effects on sodium channel function cause adverse effects
Solution Approach 1:
The patent applies segmentation by dividing the sodium channel function into specific subunit targets (SCN8A vs. other SCN subunits). Instead of blocking all sodium channels non-specifically, the invention segments the approach to target only SCN8A-containing channels through splice-modulating oligonucleotides that specifically alter SCN8A pre-mRNA splicing, thereby reducing SCN8A subunit expression while leaving other sodium channel subunits unaffected.
Solution Approach 2:
The patent applies local quality by creating a targeted therapeutic effect specifically at the SCN8A subunit level. The splice-modulating oligonucleotides are designed to bind to specific sequences in SCN8A pre-mRNA and modulate splicing in a localized manner, affecting only SCN8A isoform expression patterns without altering the function or expression of other sodium channel subunits, thus achieving seizure control without the adverse effects of global sodium channel blockade.
2Reliability
If SCN8A function is reduced to rebalance excitatory/inhibitory imbalances, then neuronal excitability is reduced, but precision in modulating only SCN8A must be maintained
Solution Approach 1:
The patent applies the intermediary principle by using splice-modulating oligonucleotides as a mediator between the therapeutic goal (reducing SCN8A function) and the target (SCN8A pre-mRNA). These oligonucleotides serve as intermediate agents that specifically bind to SCN8A pre-mRNA sequences and modulate splicing to favor inclusion of exon 18N or exclusion of exon 18A, thereby producing SCN8A isoforms with reduced function or altered properties, achieving precise modulation without directly interfering with other sodium channel subunits.
Solution Approach 2:
The patent applies parameter changes by altering the splicing parameters of SCN8A pre-mRNA to change the isoform expression profile. Specifically, the splice-modulating oligonucleotides change the splicing parameters to increase inclusion of exon 18N (which introduces a premature stop codon) or exclude exon 18A, thereby changing the functional parameters of SCN8A channels without affecting other sodium channel subunits, achieving precise and selective modulation.
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
The SMOs effectively reduce neuronal excitability and seizure susceptibility by selectively targeting SCN8A isoforms, providing a therapeutic approach for Dravet Spectrum disorders with fewer adverse effects compared to general sodium channel blockers.
Implementation Method 1
the SMO sequence specifically binds to a sequence in the SCN8A pre-mRNA
Data Source
AI summary
A splice modulating oligonucleotide (SMO), is provided having a sequence designed to modulate the splicing of a SCN8A pre-mRNA, wherein the SMO sequence specifically binds to a sequence in the SCN8A pre-mRNA. Certain embodiments of the invention provide methods of using the SMOs described herein, including methods of treating or preventing epilepsy or a Dravet Spectrum disorder in subject (e.g., a mammal, e.g., a human), including the administration of an SMO or composition described herein to the subject. A method of using the SMOs is described herein to treat spinal cord injury, cancer, amyotrophic lateral sclerosis, Alzheimer's disease, traumatic brain injury, autism, hemiplegic migraine, multiple sclerosis, CNS infections, Parkinson's and Huntington's disease, or other neurological diseases or disorders in which excitotoxicity or hyperexcitability contributes to the pathology.